Regulation of the Immune Response by TGF-B: from Conception to Autoimmunity and Infection

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Regulation of the Immune Response by TGF-b: From Conception to Autoimmunity and Infection

Shomyseh Sanjabi,1,2,4 Soyoung A. Oh,3,4 and Ming O. Li3

1Institute of Virology and Immunology, Gladstone Institutes, San Francisco, California 94158 2Department of Microbiology and Immunology, University of California, San Francisco, California 94143 3Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 Correspondence: [email protected]; [email protected]

Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inﬂammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions. Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naı¨ve T-cell pool. TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral (p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue resi- dence in response to immune challenges. Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self- and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

n mammals, the innate and adaptive arms of of these innate and adaptive recognition path- Ithe immune system orchestrate host–defense ways, and their precise modes of communica- and inflammatory responses. For example, leu- tion provide a robust mechanism that stimu- kocytes of the myeloid cell lineage use germline- lates immunity and protects the host against encoded receptors to detect conserved molecu- pathogens. Nevertheless, the immune system lar patterns associated with pathogens, which tolerates antigens originating from self-, com- allows them to alert and activate the rest of the mensal organisms, and the allogeneic fetus. By immune system, including adaptive immunity. maintaining this balance between immunity Alternatively, lymphocytes of the adaptive im- and tolerance, the immune system can promote mune system express antigen-specific receptors the physiological well-being of an individual. that distinguish small differences in macromol- A pivotal and pleiotropic regulator of im- ecules and establish long-term immunity by mune responses is transforming growth factor forming immunological memory. The coupling b (TGF-b), which was first reported to control

4These authors contributed equally to this work. Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a022236

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S. Sanjabi et al.

immune cell function three decades ago (Kehrl appreciated, and TGF-b signaling is one mech- et al. 1986b). TGF-b controls the magnitude anism by which such “escaped” autoreactive T and type of immune responses against mi- cells can be controlled in the periphery, a pro- crobes, and has fundamentally important roles cess called peripheral tolerance. Although TGF- in maintaining immune tolerance and homeo- b is well known for its tolerance-inducing stasis against self- and benign antigens at steady- activities in the periphery, its contributions to state (Li et al. 2006b; Oh and Li 2013; Travis and T-cell biology clearly extend beyond its role as Sheppard 2014). In this review, we discuss how an immunosuppressive cytokine. Indeed, TGF- TGF-b regulates the differentiation and func- b also has important functions in the develop- tion of different classes of leukocytes, and how ment of several T-cell lineages. it modulates immune activities, from concep- In the thymus, the differentiation of con- tion to autoimmunity and infection. ventional CD8þ T cells requires both TCR engagement and signaling through the common g-chain family cytokine interleukin 7 (IL-7) TGF-b IN THE IMMUNE SYSTEM (Park et al. 2010). Consequently, maintaining expression of the IL-7 receptor on CD8þ T- T Cells cell precursors is critical given the role of IL-7 signaling in the specification of the CD8þ T-cell Thymic Development fate. TGF-b regulates the expression of the IL-7 T cells arise from bone marrow–derived precur- receptor a-chain (IL-7Ra) in developing CD8þ sors that traffic to the thymus, where their de- T cells (Ouyang et al. 2013), thus supporting IL- velopmental process is completed. In the thy- 7 signaling, and therefore CD8þ T-cell lineage mus, T-cell precursors are exposed to a variety commitment. Mechanistically, TGF-b signaling of extrinsic signals, for example, peptides pre- promotes IL-7Ra expression on CD8þ thymo- sented by major histocompatibility complexes cytes by suppressing the expression of the (MHCs), costimulation, and cytokines, which transcriptional repressor Gfi-1, a known inhib- stimulate molecular changes that cause differ- itor of Il7ra expression in CD8þ T cells (Park entiation into distinct T-cell lineages. The dif- et al. 2004). This cross talk between TGF-b ferentiation of conventional CD4þ and CD8þ and IL-7 signaling pathways is an essential as- ab T cells requires T-cell receptor (TCR) en- pect of conventional CD8þ T-cell development gagement that follows the Goldilocks principle, (Fig. 1A). in which both too little and too much TCR TGF-b also regulates the development of signaling are detrimental to the successful de- multiple subsets of regulatory and innate-like velopment of mature T cells. T-cell precursors T cells. Thymus-derived CD4þCD25þFoxp3þ require appropriate TCR signaling to trigger regulatory T (tTreg) cells, invariant natural kill- their survival and maturation, a process termed er T (iNKT) cells, and CD8aaþTCRabþ intra- positive selection. “Too little” signaling results epithelial lymphocytes (IELs) share a common in death of the developing T cells. Yet “too thread: their development requires high-affini- much” TCR signaling, which reflects strong re- ty interactions with MHC-presenting self-li- activity to self-peptide:MHC complexes, can gands, which are referred to as agonist ligands also cause death of the developing T cell. This (Stritesky et al. 2012). Because TGF-b promotes process of negative selection, a key aspect of the survival of precursor populations for each of central tolerance, eliminates autoreactive T cells these lineages (discussed in more detail below), from the T-cell repertoire. However, this process it functions as a unifying molecule to promote is not complete, and some autoreactive T cells the differentiation of T-cell populations that re- mature in the thymus and exit to the periphery, quire strong agonist ligands for their develop- where they must be kept in check to prevent the ment (Fig. 1A). development of autoimmunity. The immuno- Treg cells are essential for the maintenance suppressive functions of TGF-b have long been of immune tolerance (Josefowicz et al. 2012).

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Regulation of Immunity by TGF-b

A Thymus Periphery Strong agonist TGF-β IL-7R + + ligand selection CD4 CD4 CD8αα+ Apoptosis TGF-β CD4+ Lineage B IL-7-dependent survival tTreg + CD8 commitment Low-affinity T cells iNKT β IL-7R TGF- CD8+ CD8+

D CD8+ T-cell differentiation TGF-β SLEC Apoptosis C β β TGF- TGF- CTL TGF-β CD103 TRM CD8+

+ CD4+ E CD4 T-cell differentiation + Retinoic acid and IL-2 pTreg TCR:MHC-driven T-cell activation Autoreactive/high-affinity T cells + IL-6 Th1 Th17 TGF-β + IL-4 Th2 Th9

+ IL-21, IL-23 TFH

Figure 1. Regulation of T cells by transforming growth factor b (TGF-b). (A) TGF-b promotes the thymic development of multiple T-cell lineages. TGF-b supports the survival of thymus-derived Treg (tTreg), invariant natural killer T (iNKT), and CD8aaþ T-cell precursors, and thus promotes the development of T-cell populations that are induced by strong agonist ligands. TGF-b also supports the development of conventional CD8þ T cells by promoting thymocyte expression of interleukin (IL)-7Ra.(B) TGF-b regulates peripheral T-cell homeostasis by promoting IL-7-dependent survival of low-afﬁnity T cells, through its control of thymocyte IL-7Ra expression, and by (C) inhibiting T-cell receptor (TCR)-driven activation of autoreactive or high- afﬁnity T cells. (D) In early stages of CD8þ T-cell differentiation, TGF-b inhibits cytotoxic T lymphocyte (CTL) development. However, TGF-b also promotes the apoptosis of short-lived effector cells (SLECs) and the differentiation of CD103-expressing tissue resident memory (TRM) cells. (E) Whereas TGF-b inhibits T helper 1 (Th1)- and Th2-cell differentiation, TGF-b (in concert with other factors) promotes the development of peripheral Treg (pTreg), Th17, Th9, and T follicular helper (Tfh) cells.

Although Treg cells can be generated in the matic reduction in the frequency of Foxp3þ periphery by the conversion of conventional thymocytes (Liu et al. 2008). Although a con- naı¨ve CD4þ T cells, the thymus gives rise to served DNA sequence for Smad3 binding is the majority of Treg cells, which are referred present in Foxp3 gene regulatory sequences to as thymus-derived Treg (tTreg) cells (She- (Tone et al. 2008), TGF-b signaling is dispen- vach and Thornton 2014). The development sable for the induction of Foxp3 expression in of tTreg cells is driven by a combination of tTreg cells (Zheng et al. 2010; Schlenner et al. stringent TCR interactions, costimulation, 2012), showing that TGF-b does not promote and cytokine signals. The TGF-b signaling tTreg-cell development by directly regulating pathway plays a role in the early development Foxp3 expression. Instead, TGF-b signaling of tTreg cells, and 3- to 5-day old mice lacking promotes tTreg-cell development by antagon- the TGF-b type I receptor (TbRI) show a dra- izing thymic-negative selection, and therefore

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promoting the survival of tTreg-cell precursors TGF-b was first shown to immunoregulate (Ouyang et al. 2010). and reduce proliferation of human T cells iNKT cells recognize lipids presented by the through studies in cell culture (Kehrl et al. MHC class I–like molecule CD1d, and possess 1986b). During priming, TGF-b inhibits T- qualities that are reminiscent of both the innate cell proliferation by inhibiting transcription of and adaptive immune responses. This subset of the Il2 gene and suppressing IL-2 production lipid-sensing T cells has been shown to play (Brabletz et al. 1993; Tzachanis et al. 2001). At both beneficial and pathogenic roles in a variety the molecular level, Smad3 mediates this sup- of inflammatory and disease conditions (Bren- pression, as both Smad3-deficient CD4þ and nan et al. 2013). Strong agonist ligand interac- CD8þ T cells are not sensitive to IL-2 inhibition tions are also thought to promote iNKT-cell mediated by TGF-b (McKarns et al. 2004; development (Stritesky et al. 2012), and, as ob- McKarns and Schwartz 2005). TGF-b also in- served with tTreg cells, TGF-b signaling appears hibits the expression of several cell-cycle regu- to play a critical role in promoting the survival lators in primary T cells and T-cell lines (Rue- of iNKT-cell precursors. T-cell-specific deletion gemer et al. 1990; Genestier et al. 1999; Nelson of the TGF-b type II receptor (TbRII) leads to a et al. 2003; Wolfraim et al. 2004). However, reduction of both thymic and peripheral iNKT whether TGF-b inhibits T-cell priming under cells (Li et al. 2006a; Marie et al. 2006; Doisne inflammatory conditions in vivo and the exact et al. 2009), which results, in part, from in- mechanism by which this regulation may occur creased apoptosis of immature precursor cells are unclear. in the absence of TGF-b signaling (Doisne Befitting the pleiotropic nature of TGF-b, et al. 2009). its ability to regulate T-cell proliferation de- CD8aaþTCRabþ IELs are innate-like T pends on the status of T-cell differentiation cells that play important roles in intestinal ho- and the cumulative signaling pathways involved meostasis (Cheroutre et al. 2011). The develop- in cell activation. For example, TGF-b can in- ment of these innate-like T cells is thought to hibit the proliferation of naı¨ve but not activat- occur both in and outside the thymus, and also ed T cells, an effect associated with decreased appears to be driven by high-affinity TCR inter- TbRII expression on activated T cells (Cottrez actions with their selection ligands (Pobezinsky and Groux 2001; Sanjabi et al. 2009). Addition- et al. 2012). In the absence of TGF-b signaling, ally, in naı¨ve T cells, CD28 engagement sends a the CD8aaþTCRabþ IEL population is de- costimulatory signal that abrogates TGF-b increased, which is partially driven by a reduction hibition of proliferation (Sung et al. 2003), en- in numbers of thymic precursors of these in- suring that TGF-b does not inhibit the ability nate-like T cells (Konkel et al. 2011). of activated antigen-presenting cells (APCs) to Collectively, the studies of tTreg cells, iNKT prime naı¨ve T cells. cells, and CD8aaþTCRabþ IEL development T-cell proliferation must be properly regu- highlight the importance of TGF-b signaling in lated to maintain homeostasis under steady- mediating the survival of a precursor popula- state conditions and during immune chal- tion in the ontogeny of multiple T-cell lineages. lenges. The absence of TGF-b signaling alters homeostasis of both CD4þ and CD8þ T cells. For example, loss of TGF-b signaling in mice, in Peripheral Homeostasis which CD4þ T cells are engineered to express a An effective immune system must maintain a single TCR, results in a dramatic reduction of diverse pool of naı¨ve T cells within the confines the peripheral T-cell population (Li et al. 2006a; of a relatively constant number of peripheral T Ouyang et al. 2013). TGF-b supports the ho- cells. TGF-b critically contributes to the main- meostasis of peripheral CD4þ T cells by pro- tenance of an effective naı¨ve T-cell population moting IL-7Ra expression in the thymus dur- by regulating T-cell proliferation, homeostasis, ing T-cell development, which allows naı¨ve and repertoire diversity. peripheral CD4þ T cells to sense IL-7 for their

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Regulation of Immunity by TGF-b

survival (Ouyang et al. 2013). Interestingly, this homeostasis by TGF-b can lead to cell transfor- regulation is particularly important for the sur- mation, as expression of a dominant-negative vival of low-affinity CD4þ T cells (Fig. 1B). This form of TbRII (dnTbRII) in T cells causes phenomenon was shown in studies using trans- mice to develop lymphoma (Lucas et al. genic expression of the AND TCR that possesses 2004). Interestingly, expression of dnTbRII, a higher affinity for its positive selection ligand but not deletion of TbRII, causes a CD8þ T- in the MHC H-2k background than that in the cell lymphoproliferative disorder (Ishigame H-2b background (Smith et al. 2001; Ouyang et al. 2013a). These findings suggest that either et al. 2013). In both genetic backgrounds, re- the dnTbRII exerts a dominant function inde- gardless of high or low affinity for the positive pendent of its inhibiting TGF-b signaling, or selection ligand, TbRII-deficient AND T cells that T-cell homeostasis is regulated by TGF-b express lower levels of IL-7Ra than their wild- signaling in a dose-dependent manner (Ishi- type counterparts. However, comparison of the game et al. 2013a). transgenic T cells between the two genetic back- CD8þ T cells undergo massive clonal ex- grounds showed that TbRII-deficient AND T pansion after becoming activated in response cells in the high-affinity background (i.e., to pathogens, followed by apoptosis-mediated H-2k) express greater levels of IL-7Ra than even contraction on pathogen clearance. TGF-b wild-type AND T cells in the low-affinity back- plasma levels increase in response to acute Lis- ground (i.e., H-2b), showing that TGF-b signal- teria monocytogenes (LM) infection. Mice ex- ing and TCR signal strength both contribute to pressing OTI TCR transgenic T cells, specific IL-7Ra expression. Thus, the absence of TGF-b for MHC I–restricted ovalbumin SIINFEKL signaling causes a more profound defect in peptide, were crossed to dnTbRII animals and IL-7Ra expression and correspondingly results further crossed to RAG12/2 animals to elimi- in poor peripheral homeostasis in T cells bearing nate V(D)J recombination of endogenous TCR low-affinity TCRs. Notably, Tgfb12/2 mice locus. Naı¨ve T cells from corresponding OTI- show altered diversity of CD4þ TCRs in the pe- dnTbRII-RAG12/2 and OTI-RAG12/2 ani- riphery, but not in the thymus (Robinson and mals were adoptively cotransferred into wild- Gorham 2007), which likely reflects repertoire type animals that were then infected with a re- changes caused by the preferential loss of low- combinant LM-expressing chicken ovalbumin affinity CD4þ T cells. (LM-OVA). Using this system, it was shown TGF-b signaling is also important for the that TGF-b plays a major role in maintaining regulation of peripheral CD8þ T cells. Defects T-cell homeostasis during CD8þ T-cell clonal in TGF-b signaling result in altered homeostasis expansion by promoting apoptosis of short- and aberrant activation of CD8þ T cells (Lucas lived effector CD8þ T cells that are enriched et al. 2000; Johnson and Jameson 2012; Zhang among the cells expressing the killer-cell lec- and Bevan 2012). However, mice expressing cer- tin-like receptor subfamily G member 1 tain transgenic TCRs do not show changes in (KLRG1) (Fig. 1D) (Sanjabi et al. 2009). Simi- CD8þ T-cell homeostasis on loss of TGF-b sig- larly, adding TGF-b to cultures of human T cells naling (Lucas et al. 2006). These differences may at 72 h postactivation induces T-cell death (Sil- be explained by differences in the affinity of each lett et al. 2001; Hernandez-Garay and Mendez- of these transgenic TCRs for self-peptide MHC Samperio 2003). However, using a model in complexes. As such, T cells expressing high-af- which TbRII expression is specifically inactivat- finity TCRs undergo greater homeostatic prolif- ed in CD8þ T cells, it was shown that higher eration than T cells expressing low-affinity proliferation rather than less apoptosis was TCRs (Kieper et al. 2004). Indeed, homeostatic responsible for expansion of Tgfbr22/2 CD8þ proliferation of CD8þ T cells with defective T cells after pathogenic challenge (Hu et al. TGF-b signaling depends on TCR and MHC 2015). Although both dnTbRII-expressing class I (Fig. 1C) (Johnson and Jameson 2012). and Tgfbr22/2 mouse models show an increase At its extreme, loss of control of CD8þ T-cell in the ratio of KLRG1þ short-lived effector T

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cells compared with KLRG12 memory precur- (Strainic et al. 2012), stimulates TGF-b produc- sor T cells, the exact mechanism of this increase tion and converts CD4þ T cells into Treg cells. during effector CD8þ T-cell expansion remains Indeed, TGF-b promotes regulatory activity unclear. in naı¨ve CD4þ T cells (Yamagiwa et al. 2001) by inducing Foxp3 expression (Chen et al. 2003b; Selvaraj and Geiger 2007) and pTreg- Differentiation cell differentiation. Foxp3 then provides a pos- TGF-b broadly inhibits T-cell activation by in- itive feedback loop in TGF-b signaling by terfering with TCR signaling (Chen et al. down-regulating TGF-b-induced expression of 2003a). It also specifically suppresses cytotoxic the inhibitory Smad7 (Fantini et al. 2004). T lymphocytes (CTL) and T helper 1 (Th1) and TGF-b plays both direct and indirect roles T helper 2 (Th2) lymphocyte subset differenti- in Foxp3 expression. The Foxp3 gene contains ation by inhibiting the expression of lineage- an enhancer element that allows for direct bind- defining transcription factors such as T-bet ing of Smad3 and nuclear factor of activated T and GATA-3, respectively (Fig. 1D,E) (Gorelik (NFAT) cells (Tone et al. 2008) to a conserved et al. 2000, 2002; Heath et al. 2000). TGF-b was DNA sequence (Xu et al. 2010; Zheng et al. also shown to suppress Th1 differentiation by 2010). TGF-b also promotes locus activation inhibiting the expression of Stat4 (Lin et al. by opposing the recruitment of a DNA methyl- 2005), a transcription factor whose expression tranferase to the Foxp3 locus (Josefowicz et al. is activated in response to IL-12 signaling. TGF- 2009). As an indirect mechanism, TGF-b in- b regulates T-bet and Stat4 expression to con- duces expression of the adaptor Nedd4 family trol Th1-cell differentiation in culture at distinct interacting protein 1 (Ndfip1), which promotes stages. Indeed, repressing Stat4 activation in- JunB degradation through the E3 ubiquitin hibits interferon g (IFN-g) production during ligase Itch, and suppresses IL-4 production to the priming phase, whereas loss of T-bet expres- support pTreg-cell differentiation (Beal et al. sion impairs IFN-g production during the re- 2011). However, the presence of inflammatory call response, that is, the restimulation of T cells cytokines and strong costimulatory signals po- after initial priming (Lin et al. 2005). Mecha- tently inhibits Foxp3 induction by TGF-b (Wei nistically, Smad2 and Smad3 transcription fac- et al. 2007; Molinero et al. 2011; Battaglia et al. tors may have a redundant role in TGF-b-me- 2013). These findings show that pTreg-cell dif- diated inhibition of Th1-cell differentiation ferentiation is modulated by the microenviron- (Takimoto et al. 2010; Gu et al. 2012). The ment, with highly inflammatory conditions fa- Smad pathway also contributes to the inhibition voring effector over Treg-cell generation. of Th2-cell differentiation by TGF-b, by induc- TGF-b also regulates Th17-cell differentia- ing the expression of Sox4, a transcription factor tion (Bettelli et al. 2006; Veldhoen et al. 2006a; that can bind to GATA-3 (Kuwahara et al. 2012). Li et al. 2007; Manel et al. 2008; Yanget al. 2008; Retroviral expression of wild-type Sox4, but not Gutcher et al. 2011). Th17 cells express the Sox4 mutants lacking the ability to interact with lineage-specific transcription factor RAR (reti- GATA-3, inhibits Th2 cytokine production in noic acid receptor)-related orphan receptor C CD4þ T cells (Kuwahara et al. 2012). (RORC) in humans (and RORgt in mice) and In contrast to its role in inhibiting Th1 produce many cytokines, including IL-17A, IL- and Th2-cell differentiation, TGF-b promotes 17F, IL-21, IL-22, and granulocyte-macrophage the development of peripheral regulatory T colony-stimulating factor (GM-CSF) (Ivanov (pTreg), Th17, Th9, and Tfh (follicular helper et al. 2006; Korn et al. 2009). RORgt expression T) cells (Fig. 1E). Suboptimal stimulation of is induced by IL-21 or IL-23, and TGF-b togeth- T cells, for example, using an altered peptide er with IL-6 amplifies RORgt-dependent Th17- ligand (Windhagen et al. 1995), low-dose anti- cell differentiation (Zhou et al. 2007). Although gen (Gunnlaugsdottir et al. 2005; Kohyama et RORgt expression is activated independently of al. 2005), or absence of complement signaling Smad2 and Smad3 (Takimoto et al. 2010),

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Regulation of Immunity by TGF-b

Smad2 has been shown to directly associate TGF-b cooperates with the Notch pathway with RORgt to enhance Th17-cell differentia- and IL-4 to induce IL-9þIL-10þ Th9 cells. These tion (Martinez et al. 2010). In addition, TGF-b cells have effector rather than regulatory func- promotes Th17-cell differentiation by inhibit- tion, despite their ability to produce abundant ing the expression of the transcription factors levels of IL-10 (Dardalhon et al. 2008; Elyaman Stat4 and GATA-3 (Das et al. 2009), Eomeso- et al. 2012). They also play a critical and non- dermin (Eomes) (Ichiyama et al. 2011), and redundant role in host-protective type 2 immu- growth factor independent 1 (Gfi-1) (Zhu nity against gastrointestinal infection with par- et al. 2009), thus preventing Th1- and Th2- asitic worms (Licona-Limoń et al. 2013). The cell differentiation. TGF-b also represses the ability of TGF-b and IL-4 to promote Th9-cell expression of Blimp-1, a transcription factor differentiation is enhanced by OX40 costimu- that limits Th17-cell differentiation (Salehi et lation, which activates TRAF6 (the ubiquitin al. 2012). Thus, TGF-b promotes the differen- ligase tumor necrosis factor [TNF] receptor-as- tiation of Th17 cells both directly and indirect- sociated factor 6) and, in turn, the noncanoni- ly by inhibiting T-cell differentiation into other cal nuclear factor (NF)-kB pathway (Xiao et al. cell lineages. 2012). Additionally, Smad2 and Smad3 cooper- Th17 cells can be both immunoregulatory ate with IL-4-induced interferon regulatory and pathogenic (Sharma et al. 2013). Genera- factor 4 (IRF4) at the Il9 locus, where they dis- tion of regulatory Th17 cells is promoted by the place binding of enhancer of zeste homolog combination of TGF-b and IL-6 (Esplugues 2 (EZH2), causing derepression of chromatin et al. 2011; Chalmin et al. 2012; Zhao et al. modification in the locus (Tamiya et al. 2013; 2012). Pathogenic Th17 cells, however, require Wang et al. 2013). The exact contribution further stimulation with IL-23 (McGeachy et al. of TGF-b signaling to the various biological 2007; Chikuma et al. 2012; Lee et al. 2012). functions of Th9 cells remains to be further ex- Pathogenic Th17 cells can also be induced in plored. cell culture without TGF-b, in the presence of Tfh cells are an important component of IL-6, IL-1b, and IL-23 (Ghoreschi et al. 2010; humoral immunity as they help B cells generate Lee et al. 2012). At low concentrations, TGF-b antigen-specific antibody responses, and their synergizes with IL-6 and IL-21 to promote differentiation depends on the transcription IL-23 receptor expression and Th17-cell differ- repressor Bcl6 (Crotty 2011). Together with entiation, whereas high TGF-b concentrations IL-12 and IL-23, TGF-b is an important cofac- repress IL-23 receptor expression and promote tor for the early differentiation of human Tfh Treg-cell differentiation (Zhou et al. 2008). In cells in cell culture (Schmitt et al. 2014). Inter- Th17 cells, TGF-b also differentially regulates estingly, TGF-b signaling in mouse CD4þ IL-22 and IL-17 expression. In the absence of T cells was also shown to be required for Tfh- TGF-b, IL-6 induces IL-22 (Basu et al. 2012); cell development, although by using a different however, in the presence of TGF-b, expres- mechanism than what was shown in human sion of cMaf, a repressor of Il22 gene expression, cells. In response to influenza infection, TGF- is induced (Rutz et al. 2011). Such oppos- b suppressed the expression of the high-affinity ing effects of TGF-b on Th17-associated cyto- IL-2 receptor on virus-specific CD4þ T cells, kines may contribute to the regulatory or and dampened IL-2-induced Stat5 signaling pathogenic functions of these cells. Intriguing- and mammalian target of rapamycin (mTOR) ly, Th17 cells transdifferentiate into regulatory activation in Tfh precursor cells (Marshall et al. T cells in a TGF-b- and aryl hydrocarbon re- 2015). ceptor (AhR)-dependent manner at the resolu- TGF-b plays an active role in the develop- tion of inflammation (Gagliani et al. 2015), ment and maintenance of IELs that reside in the thus further showing the role of TGF-b in the epithelial layer of the mucosal lining and have plasticity and switch between immunity and immediate effector functions. As already dis- tolerance. cussed, TGF-b signaling is required for the thy-

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mic development of CD8aaþTCRabþ IELs, factors reduces TbRII and CD103 expression. and also maintains CD8a expression on periph- A residual amount of T-bet is required for eral T cells (Konkel et al. 2011). Once in the expression of IL-15R and IFN-g, thus promot- epithelium, IELs are maintained by the interac- ing TRM survival and effector function, respec- tion between the cell-surface proteins CD103 tively (Mackay et al. 2015). A deeper under- (aEb7) and epithelial (E)-cadherin (Cepek standing of how TRMs are developed and et al. 1993; Schon et al. 1999). CD103 shares maintained long term in various tissues will the b7 subunit with a4b7, an integrin required shed more light on the exact contribution of for lymphocyte migration to the gut. TGF-b TGF-b signaling to the development and func- induces the expression of aE and enhances tion of these memory cells. the constitutive expression of b7, leading to increased CD103 expression at the surface of IELs Tolerance (Suzuki et al. 2002; Kang et al. 2011). One subset of IELs, tissue-resident memory Mice with impaired or total loss of TGF-b sig- T cells (TRMs), are noncirculating memory naling in T cells develop severe autoimmunity, cells that are maintained in the mucosal tissue, which shows the importance of TGF-b in con- near the site of the ﬁrst antigen encounter (Cau- trolling T-cell tolerance (Gorelik and Flavell ley and Lefrancois 2013; Schenkel and Masopust 2000; Li et al. 2006a; Marie et al. 2006). The 2014). Most TRMs express CD69 and CD103 breach of tolerance that occurs without TGF-b (Casey et al. 2012; Mackay et al. 2013; Skon signaling is not solely caused by altered activity et al. 2013). Environmental cytokines, includ- of Treg cells (Li et al. 2006a; Marie et al. 2006), ing TGF-b, IL-33, and TNF, induce repression suggesting that a major mechanism by which of Kru¨ppel-like factor 2 (KLF2) expression and TGF-b maintains tolerance is by directly regu- its target gene S1pr1. Thus, repressing sphingo- lating autoreactive T cells. This direct regulation sine-1-phosphate receptor 1 (S1P1) and en- is evident in a transgenic diabetes mouse model hancing CD69 and CD103 expression allows in which loss of TGF-b signaling in activated the maintenance of TRMs in the tissue (Mackay diabetogenic CD4þ T cells, but not Treg cells, et al. 2013; Skon et al. 2013). TGF-b is a potent induces disease (Ishigame et al. 2013b). In ad- inducer of CD103 expression by CD8þ T cells dition, in the intestine, TGF-b signaling limits (Fig. 1D) (El-Asady et al. 2005; Casey et al. tissue damage by diverting pathogenic CD4þ T 2012). Inactivation of TbRII expression in cells to a nonpathogenic phenotype (Reis et al. CD8þ T cells results in a defect in the retention 2013). Moreover, the control of autoreactive T of intestinal TRMs in the IELs, most likely a cells by Treg cells in vivo may also occur through result of the lack of CD103 expression (Zhang TGF-b signaling. Activated human and murine and Bevan 2013). In an oral model of LM infec- Treg cells express the glycoprotein A repetitions tion, TGF-b signaling in CD8þ T cells was re- predominant (GARP) protein, which associ- quired for the rapid generation of memory pre- ates with the latent form of TGF-b, resulting cursor cells that give rise to TRMs in the gut in cell-surface expression of TGF-b on Treg cells (Sheridan et al. 2014). In another oral infection (Stockis et al. 2009; Tran et al. 2009; Wang et al. study with Yersinia pseudotuberculosis, TGF-b 2009; Edwards et al. 2013). Indeed, active TGF- signaling was required for the generation of b can be generated from the membrane-bound the CD103þ TRMs, but dispensable for the complex of GARPand latent TGF-b (Wanget al. generation of CD1032 TRMs that reside in the 2012). The activation of latent complexes of lamina propria and cluster with CD4þ T and TGF-b has been reviewed (Robertson and Rif- CX3CR1þ myeloid cells (Bergsbaken and Bevan kin 2016). 2015). Additionally, the development of TRMs Interestingly, recent studies indicate that in the skin depends on TGF-b-mediated repres- loss of TGF-b signaling in mature T cells is sion of T-bet and loss of Eomes expression, not sufﬁcient to induce autoimmunity. In stark while forced expression of these transcription contrast to mice in which Tgfbr2 inactivation

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Regulation of Immunity by TGF-b

occurs during the double-positive thymocyte 1992). Furthermore, TGF-b can promote B-cell stage of T-cell maturation (Li et al. 2006a; Marie death by inducing expression of the transcrip- et al. 2006), Tgfbr2 deletion at later stages, using tional E protein antagonist Id3 to stimulate ap- the distal Lck-Cre or a tamoxifen-induced Cre optosis in B-cell progenitors (Kee et al. 2001). in mature CD4þ T cells, does not induce devel- Studies in mice with B-cell-specific loss of opment of overt autoimmunity (Zhang and TGF-b signaling verified the cell-culture obser- Bevan 2012; Sledzinska et al. 2013). However, vations that TGF-b regulates B-cell proliferation in both models, autoimmunity can be induced and survival. Splenic B cells deficient in TbRII in Rag-deficient animals, suggesting that an expression show increased BrdU incorporation added insult of extreme lymphopenia in com- when compared with wild-type B cells, con- bination with the absence of TGF-b signaling is firming an important role for TGF-b in control- required for the loss of tolerance. Notably, TGF- ling B-cell proliferation in vivo (Cazac and Roes b signaling in double-positive thymocytes in- 2000). Mice with B-cell-specific deficiency in duces IL-7Ra expression, which serves a partic- TGF-b signaling also show an expanded popu- ularly important role in promoting the homeo- lation of innate-like B cells, termed B1 cells (Ca- static survival of low-affinity TCR CD4þ T cells zac and Roes 2000). Interestingly, TbRII-defi- (Ouyang et al. 2013). Thus, in the CD4-Cre cient B1 cells are not characterized by increased model of Tgfbr2 deletion, the absence of TGF- BrdU incorporation, suggesting that their accu- b signaling in developing T cells may create a mulation may be caused by enhanced survival lymphopenic environment, with preferential in the absence of TGF-b signaling. loss of low-affinity T cells, which favors activation of higher affinity autoreactive T cells. In Activation and Differentiation addition, TGF-b-supported survival of low-affinity CD4þ T cells may play an essential role in TGF-b regulates B-cell activation by inhibiting the maintenance of a novel regulatory popula- immunoglobulin synthesis and class switching tion of CD4þ T cells, termed “deletor” T cells, to the majority of IgG isotypes (Kehrl et al. which contributes to the control of T-cell rep- 1986a, 1991). Although mice with a B-cell-spe- ertoire diversity and homeostasis. These deletor cific deficiency in TGF-b signaling do not show T cells limit the expansion of T-cell clones in a signs of overt autoimmunity, these cells show a TCR-specific manner by outcompeting other T more activated phenotype, are hyperresponsive cells for subthreshold TCR ligands (e.g., positive to normally weak immunogens, and produce selection ligands) that likely promote survival anti-dsDNA antibodies (Cazac and Roes 2000). signals without causing overt T-cell activation In contrast to TGF-b inhibiting IgG class (Singh et al. 2012). switching, TGF-b promotes B-cell production of IgA antibodies (Coffman et al. 1989; Sonoda B Cells et al. 1989; Kim and Kagnoff 1990; Lebman et al. 1990; Ehrhardt et al. 1992; van Vlasselaer et al. Proliferation and Survival 1992), which provide an important defense Early studies showed that TGF-b inhibits pro- mechanism at mucosal barriers (Fig. 2) (Cerutti liferation of mature human and immature mu- et al. 2011). Induction of IgA class switching by rine B cells (Kehrl et al. 1986a; Petit-Koskas et al. TGF-b is associated with increased transcrip- 1988; Warneret al. 1992). Mechanistically, TGF- tion of a-germline transcripts (Lebman et al. b induces growth arrest of B cells, which has 1990; Shockett and Stavnezer 1991) because of been associated with decreased expression of binding of activated Smads and Runx3 to a tan- the cell-cycle regulator cyclin A and inactivation dem-repeat element in the a-germline tran- of the cell-cycle-dependent kinase Cdk2 (Bou- script promoter (Lin and Stavnezer 1992; Shi chard et al. 1997). TGF-b also regulates B-cell and Stavnezer 1998; Hanai et al. 1999; Pardali survival, as TGF-b signaling induces apoptosis et al. 2000; Zhang and Derynck 2000; Park et al. in the murine B-cell line WEHI (Warner et al. 2001). Mice with B-cell-specific loss of TGF-b

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S. Sanjabi et al.

TGF-β Cα IgA Runx3 R-SmadSmad4Runx3 R-SmadSmad4 RBE SBE RBE SBE

Figure 2. Regulation of IgA class switching by transforming growth factor b (TGF-b). TGF-b promotes the production of IgA antibodies by increasing the transcription of a-germline transcripts. Activated Smad3 in complex with Smad4, and Runx3 bind to Smad-binding elements (SBEs) and Runx-binding elements (RBEs), respectively, which are found in the promoter of the constant heavy chain a (Ca).

signaling also show dramatic reductions in se- In addition to a role for DCs in maintaining rum and mucosal IgA levels (Cazac and Roes T-cell tolerance through integrin-mediated ac- 2000; Borsutzky et al. 2004). Interestingly, tivation of TGF-b, studies show that DCs them- whereas Smad3-deficient mice show relatively selves can acquire a tolerogenic phenotype on normal IgA production (Yang et al. 1999), B- exposure to TGF-b in cell culture. TGF-b pro- cell-specific inactivation of Smad2 expression motes the tolerogenic properties of plasma- recapitulates the reduction in IgA observed in cytoid DCs (pDCs) by inducing pDC expres- mice with TbRII-deficient B cells. This finding sion of the tryptophan-catabolizing enzyme indicates that Smad2 has a nonredundant role indoleamine 2,3 dioxygenase (IDO) (Pallotta in controlling responses of TGF-b-regulated et al. 2011). TGF-b appears to induce expres- IgA (Klein et al. 2006). sion of this enzyme in pDCs through activation of noncanonical NF-kB signaling, which promotes IDO expression in DCs (Tas et al. 2007). Besides TGF-b, culture of pDCs with IFN-g Dendritic Cells also induces IDO expression (Mellor and Dendritic cells (DCs) are important effectors of Munn 2004). However, although pDCs treated both tolerogenic and pathogenic functions of with IFN-g and TGF-b together show short- TGF-b activity (Fig. 3A). Mice with myeloid term tolerogenic functions, only pDCs cultured or DC-specific loss of the av integrins, which with TGF-b alone show long-term IDO-depen- play key roles in integrin-mediated activation of dent tolerogenic activity (Pallotta et al. 2011). TGF-b, develop colitis, showing that DCs play TGF-b also has an inhibitory effect on DC an important role in T-cell tolerance mediated function. Indeed, exposure of DCs to TGF-b in by TGF-b (Lacy-Hulbert et al. 2007; Travis culture represses the antigen presentation capa- et al. 2007). A subset of mucosal CD103þ DCs bilities and maturation status of developing also specifically promote tolerance by inducing DCs (Nandan and Reiner 1997; Yamaguchi pTreg-cell differentiation (Coombes et al. 2007; et al. 1997; Piskurich et al. 1998; Geissmann Sun et al. 2007) likely by enabling integrin-me- et al. 1999; Zhang et al. 1999b). TGF-b may diated activation of TGF-b (Paidassi et al. 2011; also exert control over DC function in part Worthington et al. 2011). From a pathogenic by regulating DC responses to inflammatory perspective, DC-mediated activation of latent stimuli. Whereas TGF-b treatment of human TGF-b also contributes to Th17-cell differenti- monocyte-derived DCs that are not exposed ation in vivo and the development of experi- to other inflammatory stimuli has no effect mental autoimmune encephalomyelitis (EAE) on DC-induced T-cell proliferation, human (Acharya et al. 2010; Melton et al. 2010). monocyte–derived DCs exposed to TGF-b be-

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Regulation of Immunity by TGF-b

A Tolerogenic Pathogenic

MHC TCR pTreg APC Th17 αvβ8 LAP: TGF-β

B Langerhans cell

TGF-β TGF-β-dependent Development Maintenance

Epidermis

Figure 3. Regulation of dendritic cells by TGF-b.(A) Dendritic cells (DCs) are key effectors of TGF-b activity. TGF-b is produced in a latent form in which the mature TGF-b is noncovalently associated with the latency- associated peptide (LAP). Release of TGF-b from its association with LAP is a critical step in activation of the cytokine. Integrin-mediated activation of TGF-b by DCs promotes the generation of peripheral Treg (pTreg) cells that possess important tolerogenic functions, and induces the differentiation of pathogenic Th17 cells. (B) Langerhans cells are specialized DCs of the epithelia that depend on TGF-b for their development and maintenance. Autocrine TGF-b signaling is required for the maintenance of this cell population.

fore lipopolysaccharide (LPS) stimulation in- expression of MHC class II and costimulatory duce a lower degree of T-cell proliferation molecules when compared with their wild-type than LPS-only-treated counterparts (Fogel- counterparts (Ramalingam et al. 2012). Yet, Petrovic et al. 2007). Furthermore, human mice with CD11c-Cre-mediated deletion of monocyte-derived DCs pretreated with TGF-b Tgfbr2 in DCs succumbed to a systemic auto- also produce reduced levels of a variety of immune disorder, the major manifestation of inflammatory mediators in response to Toll- which is gastritis. Gene-expression analyses of like receptor (TLR) or cytokine stimulation TbRII-deficient splenic and mesenteric lymph (Fogel-Petrovic et al. 2007). Notably, the ability node DCs indicated some changes in cytokine, of TGF-b to modulate the activation of a DC chemokine, and chemokine receptor expression is determined by the stimulation conditions. patterns, but whether and how these phenotyp- Although TGF-b can inhibit DC maturation ic alterations contribute to the manifestation of induced by cytokines, TLR ligands, or Fc-recep- autoimmunity remains unknown. In addition, tor engagement, engagement of the costimula- how TGF-b signaling affects DCs in nonlym- tory CD40 receptor overrides the suppressive phoid tissues, such as the stomach or intestines, effect of TGF-b on DC maturation (Geissmann has not been examined, and a major question et al. 1999). that remains is whether the sensitivity of DCs to Efforts to unravel how TGF-b signaling reg- TGF-b regulation is determined by the identity ulates DC function in vivo have yielded less clear and/or location of DCs. conclusions. Despite evidence supporting the TGF-b plays an important role is the biol- inhibitory effects of TGF-b on DC function in ogy of Langerhans cells, which are specialized culture, TbRII-deficient splenic DCs showed no DCs of the epithelia that possess important im- difference in their activation status, based on the munological and tolerogenic functions (Roma-

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ni et al. 2010). TGF-b was first implicated as genetic methods, for example, using CD11c- a regulator of Langerhans cells by the observa- Cre-mediated deletion of floxed Tgfb1. Indeed, tion that mice with global inactivation of Tgfb1 it has been shown that T cells themselves are the expression lack this specific DC population essential source of TGF-b for Th17 differentia- (Borkowski et al. 1996). Cell-culture studies tion (Li et al. 2007; Gutcher et al. 2011). subsequently showed that TGF-b induces Lan- gerhans cell differentiation of a variety of hu- NK Cells man-derived precursor cells (Strobl et al. 1996; Geissmann et al. 1998; Zhang et al. 1999b). The TGF-b has a general inhibitory effect on the role of TGF-b in Langerhans cell biology is fur- development and function of NK cells. In neo- ther supported by studies using mouse lines nates, blocking TGF-b signaling on NK cells with conditional deficiency of TbRI or TbRII, promotes faster NK maturation and reduces which established that TGF-b directly regulates susceptibility of neonates to viral infection the development and maintenance of Langer- (Marcoe et al. 2012). In adults, TGF-b inhibits hans cells (Kaplan et al. 2007; Kel et al. 2010; IFN-g and T-bet expression in NK cells, thus Zahner et al. 2011). Additionally, mice in which inhibiting type 1 immunity (Laouar et al. TbRII or TGF-b1 were deleted specifically in 2005; Yu et al. 2006). Reciprocally, proinflam- Langerhans cells phenocopied each other, matory cytokines can down-regulate TbRII ex- showing that this pathway, and specifically au- pression and inhibit TGF-b signaling in NK tocrine TGF-b signaling, is critical for the de- cells (Yu et al. 2006). Additionally, TGF-b ex- velopment or maintenance of Langerhans cells pressed by T cells may inhibit proliferation of (Fig. 3B) (Kaplan et al. 2007). In addition, TGF- NK cells in vivo after they become activated by b signaling increases recruitment of the tran- infection with acute lymphocytic choriomenin- scription factor PU.1 to the promoter and in- gitis virus (LCMV) (Su et al. 1991, 1993), or by tronic regions of the Runx3 gene (Chopin et al. hepatitis B virus (HBV) infection in humans 2013), which encodes a critical transcription (Sun et al. 2012). NK cells express activating factor in Langerhans cell development (Fainaru receptors at their surface, including NKG2D et al. 2004). and NKp30, whose expression is suppressed It has been proposed that, in the intestinal by TGF-b (Castriconi et al. 2003; Lee et al. lamina propria, a combination of TGF-b and 2004; Crane et al. 2010). The expression of bacterial sensing regulates the tolerogenic prop- NKG2D at the cell surface requires its associa- erties of gut DCs, largely by controlling DC pro- tion with the intracellular adaptors DAP10 or duction of TGF-b, which is suggested to direct DAP12 to stabilize the complex. Although IL-2 pTreg-cell generation (Kashiwagi et al. 2015). signaling stabilizes the cell-surface expression of Notably, although autocrine TGF-b signaling activating NKG2D–DAP10 receptor complex- confers enhanced TGF-b expression in DCs, es, TGF-b prevents this interaction by inhibit- the TGF-b-activated Smads appear to play ing the expression of DAP10 (Park et al. 2011; opposing roles in this regulation with Smad3 Sun et al. 2012). TGF-b also induces miR-183 promoting and Smad2 inhibiting TGF-b pro- expression to repress DAP12 expression, which duction. DCs that lack only Smad2 express destabilizes the NKG2D receptors at the surface higher levels of mRNA for TGF-b1 and IL-10, of NK cells and inhibits their downstream sig- and lower levels of mRNA for inflammatory cy- nals (Donatelli et al. 2014). tokines, for example, TNF-a, IL-6, and IL-12, and show tolerogenic activity. However, despite Monocytes and Macrophages the indication that autocrine TGF-b signaling promotes TGF-b production in DCs, whether Early work examining TGF-b regulation of my- DCs represent the critical source of TGF-b for eloid cells showed that TGF-b largely inhibits pTreg-cell differentiation, as proposed (Kashi- the proinflammatory response of macrophages wagi et al. 2015), remains to be validated by activated by TLR ligands or cytokine stimula-

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Regulation of Immunity by TGF-b

tion (Li et al. 2006b). However, stimulation with needed for tissue health, while tightly regulat- TGF-b alone, in the absence of TLR ligands or ing inflammatory cytokine secretion, is likely other cytokines, promotes myeloid cell produc- an essential feature in maintaining intestinal tion of several inflammatory cytokines (Wahl tolerance and homeostasis. Indeed, mice with et al. 1987; Chantry et al. 1989; Musso et al. expression of dnTbRII from the CD68 promot- 1990; Turner et al. 1990). TGF-b also induces er, which is primarily expressed in monocytes migration of monocytes and macrophages iso- and macrophages, show loss of TGF-b inhibi- lated from human peripheral blood (Wahl et al. tion of LPS-induced cytokine production. 1987), and enhances the adherent properties of These mice are also more susceptible to dextran monocytes (Bauvois et al. 1992; Wahl et al. sulfate sodium (DSS)-induced colitis, showing 1993b). The distinct effects of TGF-b on mye- that TGF-b controls monocytes and/or macro- loid cell function, which depend on the specific phages to regulate intestinal inflammation nature of the activating conditions, reflect the (Rani et al. 2011). complex and pleiotropic nature of this cytokine. The exact mechanism by which TGF-b reg- Furthermore, the regulation of myeloid cells by ulates the inflammatory response of myeloid TGF-b appears to be influenced by the identity cells in vivo remains largely unknown. However, of the cell. For example, depending on their TGF-b may promote suppression of TLR sig- anatomic origin, some subsets of macrophages naling. For example, in myeloid cells, TGF-b show more sensitivity to TGF-b signaling than induces and maintains expression of Axl (Bauer others (Fan et al. 1992). In addition, in chemo- et al. 2012), a member of the Tyro3, Axl, and taxis studies, blood monocytes, but not intesti- Mer (TAM) receptor tyrosine kinase family that nal macrophages, were found to traffic in re- inhibits innate immune inflammatory respons- sponse to TGF-b signaling (Smythies et al. es (Sharif et al. 2006; Rothlin et al. 2007). In- 2006). Nevertheless, determining whether and deed, blocking Axl increased cytokine produc- how TGF-b regulates distinct myeloid cell pop- tion after TLR stimulation (Bauer et al. 2012). ulations in vivo remains elusive. In addition, several cell-culture studies in- The intestine may be an anatomic location dicate that TGF-b may also control myeloid cell where regulation of myeloid cells by TGF-b is of activation by directly inhibiting NF-kB signal- particular importance. The intestine is a unique ing activated by innate receptors or cytokines tissue in which the maintenance of resident (Naiki et al. 2005; Choi et al. 2006; Hong et al. macrophages relies on continuous input from 2007; Lee et al. 2011). TLR engagement is a circulating monocytes (Ginhoux and Jung major pathway of microbial recognition, and 2014). In this context, TGF-b may induce traf- multiple adaptor proteins, including MyD88 ficking of monocytes and promote their differ- (myeloid differentiation primary response pro- entiation into noninflammatory macrophages tein 88), TRIF (Toll/IL-1R [TIR] domain-con- that reside in the tissue. Indeed, after prolonged taining, adaptor-inducing interferon-b), and exposure to TGF-b, human blood monocytes TRAM (TRIF-related adaptor molecule) medi- begin to acquire a less activated phenotype, il- ate signal transduction downstream from these lustrated by down-regulation of innate response innate receptors. Studies using the RAWmacro- receptor expression and reduced cytokine pro- phage cell line show that TGF-b represses duction (Smythies et al. 2005). Notably, this MyD88-dependent, but not TRIF- or TRAM- altered phenotype resembles the less inflamma- dependent, TLR signaling (Naiki et al. 2005). tory profile that characterizes human intestinal TGF-b inhibits this pathway by promoting the macrophages. These macrophages produce no ubiquitylation and degradation of MyD88 or only limited amounts of inflammatory cyto- (Naiki et al. 2005; Lee et al. 2011), which in- kines in response to a variety of stimuli, despite volves Smad6 and the E3 ubiquitin ligases maintaining their phagocytic and bacteriocidal Smurf1 and Smurf2 (Lee et al. 2011). TGF-b functions (Smythies et al. 2005). The ability of also impedes NF-kB activation by sequestering these macrophages to perform the functions the adaptor protein pellino-1 and, consequent-

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ly, disrupting the formation of a signaling com- promoting apoptosis and inhibiting cytokine plex containing IRAK1 (IL-1-receptor-associat- production (Alam et al. 1994). Despite these ed kinase 1), TRAF6, and MyD88 downstream observations, the extent to which TGF-b regu- from IL-1R/TLR activation (Choi et al. 2006). lates the granulocytic arm of the innate immune Both Smad6 and Smad7 can interact with system remains poorly understood. pellino-1 through discrete sequences in their respective MH2 domains, which allows simul- taneous interactions with the adaptor protein Mast Cells (Choi et al. 2006; Lee et al. 2010). In addition Mast cells have been predominantly associated to controlling the responses of receptors that with allergy responses, but a growing under- recognize microbial patterns, TGF-b inhibits standing of mast cell functions has identified NF-kB activation downstream from TNF-a sig- additional roles for these cells in wound healing, naling by promoting interactions between tissue repair, and infections. Similar to other Smad7 and the adaptor proteins TAB2 (TAK1 innate immune cells, TGF-b can induce chemo- binding protein 2) and TAB3. These compo- taxis and enhance the adherent properties of nents are part of the signaling complex that mast cells (Gruber et al. 1994; Olsson et al. forms after activation of the TNF-a pathway 2000; Rosbottom et al. 2002). TGF-b has been (Hong et al. 2007). These findings indicate im- reported to promote or suppress mast cell func- portant cross talk between TGF-b and NF-kB tion. As part of its negative regulatory func- signaling. How these interactions shape mye- tions, TGF-b inhibits the expression of the loid cell biology in vivo remains to be deter- high-affinity IgE receptor Fc1RI, a mechanism mined. that activates mast cells (Gomez et al. 2005). TGF-b was also reported to inhibit mast cell Granulocytes proliferation, degranulation, and production of several effector molecules (Broide et al. Granulocytes are innate immune cells that are 1989; Bissonnette et al. 1997; Gebhardt et al. identified by the presence of dense granules in 2005; Gomez et al. 2005). However, in mast their cytoplasm, and are also termed polymor- cells, TGF-b can also promote expression of phonuclear leukocytes for their distinctly inflammatory mediators, such as IL-6 and lym- shaped nuclei. This subset of innate immune photactin (Rumsaeng et al. 1997; Miller et al. cells has important functions in infection and 1999; Ganeshan and Bryce 2012). inflammation, and includes neutrophils, eosinophils, and basophils. TGF-b induces chemotaxis of both neutrophils (Brandes et al. 1991; TGF-b CONTROLS IMMUNE RESPONSES Fava et al. 1991; Reibman et al. 1991) and Fetal–Maternal Tolerance eosinophils (Luttmann et al. 1998). At the molecular level, Smad3 may be required for TGF- Treg cells are essential for suppressing destruc- b-induced neutrophil migration, as Smad32/2 tive alloantigenic immunity during pregnancy neutrophils show impaired chemotactic re- (Zenclussen 2006; Munoz-Suano et al. 2011; sponses (Yang et al. 1999). However, TGF-b Robertson et al. 2013). These cells are peripher- can also inhibit neutrophil migration by sup- ally induced, as their differentiation depends on pressing TNF-a–induced endothelial cell both paternal antigens and the conserved non- production of IL-8, a known neutrophil chemo- coding sequence-1 (CNS1) enhancer element attractant (Smith et al. 1996). Under some con- that contains a Smad-binding site at the Foxp3 ditions, TGF-b may also promote neutrophil locus (Zheng et al. 2010; Rowe et al. 2012; Sam- oxidant production (Brandes et al. 1991; Bala- stein et al. 2012). Female mice that lack CNS1 zovich et al. 1996). Alternatively, TGF-b can act have higher rates of embryo resorption when as a negative regulator of granulocytes, and in- mated with allogeneic, but not syngeneic, hibits the survival of human eosinophils by males, confirming that pTreg cells modulate

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Regulation of Immunity by TGF-b

maternal immune responses to paternal allo- higher than that of serum (Saito et al. 1993; antigens during pregnancy (Samstein et al. Nocera and Chu 1995; Loras et al. 1999). In 2012). In addition, during secondary pregnan- seminal fluid, TGF-b induces Treg-cell expan- cy, these fetal-specific Treg cells are maintained sion and promotes tolerance to paternal alloan- as a memory pool with accelerated expansion, tigens in mice (Robertson et al. 2009a). Exoge- which provides more resistance to embryo nous TGF-b delivered at conception also boosts resorption if Treg cells are partially ablated the numbers of vaginal Treg cells and helps re- (Rowe et al. 2012). The importance of pTreg- duce fetal loss in the CBA/J DBA/2J sponta- cell generation in fetal–maternal tolerance has neous abortion model (Clark et al. 2008). Thus, prompted much interest in understanding the seminal TGF-b has been implicated as a key biological source of TGF-b in this process. factor in initiating the remodeling events and The female reproductive tract (FRT) is a immunological changes that occur in the uterus rich environment for TGF-b production and during the preimplantation period of pregnan- responsiveness (Zhao et al. 1994; Polli et al. cy (Robertson et al. 2002, 2013). 1996). TGF-b production is regulated by ovar- ian sex hormones and enables several aspects of immunosuppression in the FRT at different Mucosal Immune Responses stages of the menstrual cycle (Chegini et al. Development of the Gut Barrier 1994; Takahashi et al. 1994; Wira and Rossoll 2003; Kim et al. 2005; Maurya et al. 2013). After leaving the sterile intrauterine environ- Accordingly, hormone-regulated fluctuations ment, neonates enter a world full of innocuous occur in systemic and uterine Treg-cell popula- environmental antigens, as well as harmful tions, with an estrogen-regulated increase at pathogens. Gradual and age-dependent matu- the time of ovulation (Arruvito et al. 2007). ration of the immune system fulfills several de- Additionally, in vaginal cells, estradiol regulates mands, such as preparing the skin and intestine tolerance induction and antigen presentation for colonization by commensal bacteria, toler- by mediating the local production of TGF-b izing the host for exposure to food and environ- (Wira et al. 2002; Wira and Rossoll 2003). Fur- mental antigens, and protecting against patho- thermore, endogenous TGF-b in the human genic infections (PrabhuDas et al. 2011). TGF-b endometrium suppresses the activity of uterine preserves the intestinal barrier function (Plan- NK cells (Eriksson et al. 2004, 2006). chon et al. 1994, 1999; Jarry et al. 2008), and its Several studies have linked Treg-cell expan- production in the intestine is age-dependent sion in early pregnancy with exposure to male (Zhang et al. 1999a; Maheshwari et al. 2011). seminal fluid. Semen provides both male allo- For example, rodent pups initially produce low antigens and immunomodulatory factors that levels of endogenous intestinal TGF-b, which sufficiently exert biological influences in the increase during the weaning period (Penttila FRT,such as activating cytokine gene expression et al. 1998). and eliciting changes in the abundance and Although still controversial, mammalian behavior of infiltrating leukocyte populations. milk is thought to provide an important exog- These responses promote tolerance and recep- enous source of TGF-b to the infant until it can tivity for embryo implantation (Robertson fully produce endogenous TGF-b (Prokesova 2005; Robertson et al. 2013). The mechanisms et al. 2006; Oddy and Rosales 2010; Penttila underlying immunological suppression by se- 2010). In mammalian milk, TGF-b is present men are not clearly defined but appear related, at high concentrations and may be a key immu- at least in part, to extremely high concentrations noregulatory factor for promoting intestinal of TGF-b and prostaglandin (PG)E2 (Robert- maturation (Rautava et al. 2012), IgA produc- son et al. 2002, 2009b). Seminal plasma con- tion, and tolerance induction (Letterio et al. tains high concentrations of TGF-b, nearly 1994; Hawkes et al. 1999; Kalliomaki et al. 500 ng/ml, which is approximately fivefold 1999; Lebman and Edmiston 1999; Donnet-

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Hughes et al. 2000; Saarinen et al. 2000; Ogawa ways are simultaneously genetically blocked, et al. 2004; Verhasselt et al. 2008; Verhasselt mice develop severe fulminant ulcerative colitis 2010; Arnold et al. 2011). caused by the microbially induced proinflammatory cytokines IFN-g and TNF-a (Kang et al. 2008). Microbiome Similarly, in IBD patients, Smad7 overex- The composition of the intestinal microbiota pression in mucosal T cells inhibits TGF-b sig- regulates the balance between Th17 and Treg naling, causing uncontrolled production of cells in the lamina propria and influences intes- inflammatory cytokines (Fiocchi 2001; Monte- tinal homeostasis (Honda and Littman 2012). leone et al. 2001). In IBD patients, Smad7 pro- Treg-cell numbers are increased in the colonic tein is more highly stabilized by p300-mediated lamina propria compared with other organs, posttranslational acetylation compared with and these numbers are reduced in germ-free healthy controls (Monteleone et al. 2005), po- or antibiotics-treated mice, suggesting that the tentially making the cells more resistant to Treg- nature of the microbiota affects colonic pTreg- cell-mediated suppression (Fantini et al. 2009). cell differentiation (Atarashi et al. 2011; Honda Indeed, overproduction of TGF-b has been re- and Littman 2012). A cocktail of 17 strains of ported (Feagins 2010), which may cause the loss bacteria, belonging to the clusters of Clostridi- of protective cells that produce IL-22 (Leung um species, isolated from the stool of a healthy et al. 2014). Regardless of the abundance of en- human provided bacterial antigens and a TGF- vironmental TGF-b, high Smad7 levels block b-rich environment to support the expansion TGF-b signaling in pathogenic T cells (Fiocchi of Treg cells in germ-free mice (Atarashi et al. 2001). IL-25 can limit proinflammatory cyto- 2013). Th17 cells are also induced in the small kine production and chronic intestinal inflam- intestinal lamina propria in the presence of mation (Owyang et al. 2006). TGF-b induces, members of the cytophaga–flavobacter–bac- whereas TNF-a inhibits, IL-25 production in teroides phylum, which requires TGF-b activity the human gut, and knockdown of Smad7 in- (Ivanov et al. 2008). creases IL-25 production (Fina et al. 2011). Oral administration of Smad7 antisense oligonucle- otides can restore TGF-b signaling and amelio- Inflammatory Bowel Disease rate inflammation in hapten-induced colitis IL-10 and TGF-b play nonredundant roles in (Boirivant et al. 2006), suggesting that blocking maintaining intestinal homeostasis (Fiocchi Smad7 may be a promising and safe method to 2001; Izcue et al. 2009; Feagins 2010; Jarry dampen inflammation in IBD patients (Monte- et al. 2011; Biancheri et al. 2014). IL-10 func- leone et al. 2008, 2012; Marafini et al. 2013). tions both upstream and downstream in TGF-b signaling (Fuss et al. 2002; Kitani et al. 2003). For example, IL-10 can induce TGF-b expres- Autoimmune Diseases sion and secretion in T cells of the lamina pro- Arthritis pria (Zhou et al. 1998; Fuss et al. 2002). Addi- tionally, it cooperates with TGF-b to promote Rheumatoid arthritis (RA) is an inflammatory differentiation of Treg cells (Weiner 2001; Di disorder that targets the joints and is driven by Giacinto et al. 2005), which produce more aberrant responses in T and B cells. The effects TGF-b and IL-10 (Harrison and Powrie 2013). of TGF-b on RA development appear to be de- Mutations in genes encoding components of termined by the anatomical context of cytokine TGF-b and IL-10 signaling pathways have signaling, as local versus systemic modulation been implicated in human inflammatory bow- of TGF-b activity has opposing effects on dis- el disease (IBD) (Glocker et al. 2009; Franke ease development in rodent models of RA. For et al. 2010; McGovern et al. 2010; Naviglio example, injecting TGF-b into the joints of et al. 2014). Indeed, when both of these path- Lewis rats induces synovial inflammation and

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Regulation of Immunity by TGF-b

joint swelling associated with macrophage infil- models of EAE (Johns et al. 1991; Kuruvilla et al. tration and increased expression of IL-1b (Allen 1991; Racke et al. 1991), suggesting that TGF-b et al. 1990). Correspondingly, administering a inhibits disease development. Indeed, two TGF-b blocking antibody into a joint amelio- models of EAE showed that suppression of dis- rates group A streptococci–induced arthritis ease by tolerogenic CD4þ T cells depends on (Wahl et al. 1993a). In contrast, studies in the TGF-b activity (Chen et al. 1994, 2008). In ac- collagen-induced arthritis model indicate that cordance, T-cell lines derived from patients with systemic TGF-b signaling protects against dis- stable MS produce more TGF-b than those ease development (Kuruvilla et al. 1991; Thor- from patients with active MS, suggesting that becke et al. 1992). These protective effects are, in disease severity may associate inversely with part, mediated by direct regulation of T cells, levels of TGF-b production (Mokhtarian et al. as mice with T-cell-specific expression of the 1994). dnTbRII subunit develop more severe arthritis Interestingly, TGF-b signaling also pro- (Schramm et al. 2004). motes differentiation of Th17 cells that induce EAE development. CD4þ T cells that express a dnTbRII do not differentiate into Th17 cells, Diabetes and mice expressing a dnTbRII under the con- Type 1 diabetes mellitus (T1D) is a chronic au- trol of the CD4 promoter are resistant to EAE, toimmune disease driven by immune-mediated indicating that TGF-b signaling is critical for destruction of pancreatic islet b cells. Multiple the in vivo generation of pathogenic Th17 cells models of pancreas-specific overexpression of and EAE development (Veldhoen et al. 2006b). active TGF-b show that TGF-b inhibits diabetes Furthermore, genetic studies show that auto- development (King et al. 1998; Moritani et al. crine TGF-b signaling is required for in vivo 1998; Grewal et al. 2002). Protection against Th17 differentiation, as mice with T-cell-specif- T1D is associated with the induction of tolero- ic deletion of Tgfb1 do not develop Th17 cells genic T-cell responses, suggesting that TGF-b and are resistant to EAE (Li et al. 2007; Gutcher regulates diabetogenic T cells to prevent disease et al. 2011). In contrast, cell-culture studies sug- (King et al. 1998; Moritani et al. 1998). Indeed, gest that treatment of CD4þ T cells with TGF- coadministering a TGF-b blocking antibody re- b1 produces nonpathogenic Th17 cells that fail verses the protective effects of CD3-specific an- to induce EAE (McGeachyet al. 2007; Ghoreschi tibody treatment in the nonobese diabetic et al. 2010), whereas treatment with TGF-b3 in- (NOD) model (Belghith et al. 2003). Studies duces a pathogenic Th17 population that causes using a model of diabetes in which CD4þ T cells disease (Lee et al. 2012). However, the ability of express a transgenic TCR that recognizes a pan- TGF-b3 to induce pathogenic Th17 cells in vivo creas-specific peptide clearly show the impor- (e.g., by using T-cell-specific Tgfb3 knockouts) tance of TGF-b in directly regulating the re- has not been explored. sponse of effector T cells to prevent diabetes (Ishigame et al. 2013b). Whereas deleting TbRII Systemic Lupus Erythematosus expression in activated effector T cells induces diabetes development, Treg-cell-specific loss of Systemic lupus erythematosus (SLE) is a chron- TGF-b signaling has no effect on disease path- ic autoimmune disorder characterized by au- ogenesis (Ishigame et al. 2013b). toantibody production that affects multiple organs. Administering a vector that encodes TGF-b1 enhances survival and ameliorates dis- Multiple Sclerosis ease severity in a murine model of lupus, sug- EAE is the animal model system that is com- gesting that TGF-b plays a protective role in monly used to study the central nervous system disease (Raz et al. 1995). In general, SLE pa- disorder multiple sclerosis (MS). Administering tients produce lower levels of TGF-b when com- TGF-b has a protective effect in several murine pared with healthy individuals (Ohtsuka et al.

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1998, 1999; Becker-Merok et al. 2010). Total signaling using dnTbRII rapidly eradicates the TGF-b levels were lowest in hospitalized pa- virus (Tinoco et al. 2009). However, blocking tients with active disease, suggesting that TGF- the TGF-b receptor during the early memory b production may be associated with disease phase failed to substantially enhance the antivi- severity (Ohtsuka et al. 1999). This is supported ral T-cell response or reduce viral titers in vivo by a survey of 102 SLE patients in which TGF-b (Boettler et al. 2012), suggesting that TGF-b levels associate inversely with disease severity may exert its apoptotic effect on clonally ex- (Becker-Merok et al. 2010). panding effector cells rather than on exhausted T cells (Sanjabi et al. 2009; Tinoco et al. 2009). Infection Therapeutically blocking TGF-b signaling be- Bacterial fore viral infection significantly increases viral- specific T cells; however, it also fails to improve The route by which a pathogen infects its host T-cell function or the ability of T cells to clear can determine the arm of protective immunity chronic LCMV infection. These findings sug- that the host elicits against that pathogen. For gest that the inflammatory environment and example, oral infection with Yersinia entero- the potential difference in T-cell repertoire in colitica promotes Th17-mediated immunity, mice expressing a dnTbRII in T cells may con- whereas systemic infection promotes Th1-me- tribute to their ability to clear chronic viral in- diated immunity (DePaolo et al. 2012). Vaginal fection, as originally reported by Tinoco et al. Neisseria gonorrhoeae induces TGF-b produc- (2009). In a fourth study of chronic LCMV in- tion, which inhibits a protective Th1-cell re- fection, TbRII expression was increased in sponse while promoting a Th17 response (Liu CD8þ T cells, but conditionally inactivating et al. 2012). Other mucosal pathogens, such as Tgfbr2 expression in peripheral T cells de- Citrobacter rodentium, induce Th17-cell re- creased the expansion of CD8þ T cells yet did sponses by promoting apoptosis of intestinal not affect their function or exhaustion (Zhang epithelium, and producing TLR-containing and Bevan 2013). Thus, the exact role of TGF-b apoptotic cells that induce both IL-6 and signaling on the expansion, function, and ex- TGF-b production (Torchinsky et al. 2009; haustion of CD8þ T cells during chronic viral Brereton and Blander 2010). However, without infection remains unclear. normal production of inflammatory cytokines, In human studies, serum TGF-b levels are high TGF-b levels produced by infected intesti- increased in patients with HBV or hepatitis C nal epithelium can also lead to defects in proper virus (HCV), which contributes to the liver fi- activation of T cells against mucosal pathogens, brosis often seen with these chronic viral infec- as apparent during Helicobacter pylori infection tions (Alatrakchi et al. 2007; Khorramdelazad (Beswick et al. 2011). et al. 2012; Karimi-Googheri et al. 2014). Fur- thermore, TGFB1 genetic polymorphisms have Viral been associated with higher systemic TGF-b Influenza virus neuraminidase activates latent levels and worse outcome in hepatic viral in- TGF-b (Schultz-Cherry and Hinshaw 1996), fections (Dai et al. 2008; Pereira et al. 2008). which protects the host from influenza patho- Viral-specific proteins have also been shown genesis and virus-mediated pathology in the to enhance TGF-b production and its cellular lung (Carlson et al. 2010). Although TGF-b activity. The HBV-encoded pX oncoprotein protects against excessive pathology during enhances transcriptional activity of TGF-b by acute viral infections, it can have a detrimental stabilizing the Smad complex on the transcrip- effect on T-cell immunity during chronic viral tional machinery (Lee et al. 2001), whereas the infections. For example, during LCMV infec- HCV nonstructural protein 4 (NS4) induces tion, sustained TGF-b expression and Smad2 TGF-b expression in monocytes (Rowan et al. activation cause apoptosis of virus-specific 2008). The HCV core protein can also activate CD8þ T cells, and genetic blockade of TGF-b TGF-b, and mice that overexpress HCV core

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Regulation of Immunity by TGF-b

protein through transgenic expression in the of NKT cells, which share properties of both T liver, show deregulated expression of TGF-b tar- cells and NK cells, which produce IL-17 (Cam- get genes (Benzoubir et al. 2013). Finally, TGF- pillo-Gimenez et al. 2010). Furthermore, the b produced by hepatic cells can induce Treg-cell HIV envelope protein gp120 can bind to a4b7 generation, which can further dampen antiviral integrins on naı¨ve B cells to induce TGF-b and immunity and contribute to chronic hepatic Fc receptor-like 4 (FcRL4) expression, which viral infections (Dunham et al. 2013; Karimi- causes B-cell dysfunction and inhibits their Googheri et al. 2014). proliferation (Jelicic et al. 2013). Furthermore, TGF-b1 expression is also increased in HIV- TGF-b is an important mediator of pathologi- infected patients and correlates with disease cal fibrosis, and promotes collagen deposition progression (Lotz and Seth 1993; Wiercinska- in lymphoid organs in response to HIV- or SIV Drapalo et al. 2004). HIV tat protein has been (simian immunodeficiency virus)-induced in- linked to high TGF-b secretion in infected cells flammation. This effect disrupts IL-7 produc- (Wahl et al. 1991; Zauli et al. 1992; Lotz et al. tion in lymph nodes, which can eventually con- 1994; Sawaya et al. 1998; Reinhold et al. 1999). tribute to depletion of CD4þ T cells (Estes et al. The association of viral gp160 with CD4 on 2007; Zeng et al. 2011). monocytes can also induce TGF-b production When rhesus macaques are infected with (Hu et al. 1996). TGF-b induces C-X-C chemo- SIV, they develop AIDS-like syndromes that kine receptor type 4 (CXCR4) expression on are accompanied by massive inflammation, macrophages, contributing to enhanced tro- similar to HIV-infected patients; however, Afri- pism of HIV for both CD4 T cells and macro- can green monkeys (AGM) infected with SIV phages (Chen et al. 2005). TGF-b1 production remain healthy and do not show this chronic by monocytes may also cause HIV-induced ap- inflammation (Chahroudi et al. 2012). SIV-in- optosis of CD4þ T cells and consequent deple- fected AGMs show early and strong increases in tion in vivo (Wang et al. 2001). Conversely, IL-10, TGF-b, and Foxp3 expression, which op- TGF-b represses CD4 and C-C chemokine re- pose findings in infected macaques that show ceptor type 5 (CCR5) expression, and inhibits diminished sensitivity to TGF-b signaling in T NF-kB activation, thus limiting HIV replication cells (Kornfeld et al. 2005; Ploquin et al. 2006). in intestinal macrophages (Shen et al. 2011). One of the hallmarks of AIDS is HIV-medi- Interestingly, TGF-b induces the expression of ated immunodeficiency against other patho- CD169, which is a main HIV-1 receptor ex- genic and nonpathogenic organisms. TGF-b pressed on mucosal DCs that captures virus may play an active role in this process. In HIV and transmits it to target cells; thus, TGF-b and HCV coinfections, HIV-induced TGF-b found in semen may contribute to sexual trans- expression promotes both HCV replication mission of the virus (De Saint Jean et al. 2014). and advanced liver fibrosis (Lin et al. 2008). Infecting human CD4þ T cells with HIV in- Similarly, HIV-infected macrophages produce duces TGF-b production that further promotes high levels of TGF-b and permit the survival Treg-cell generation specific to the gp120 sur- and multiplication of otherwise nonpathogenic face viral antigen (Amarnath et al. 2007; Stev- parasites (further discussed below) (Barreto- ceva et al. 2008). However, infection of Treg cells de-Souza et al. 2008). with HIV represses Foxp3 expression, reduces the generation of TGF-b, and increases IL-4 Parasitic production, thus limiting Treg-cell function (Pion et al. 2013) and likely contributing to During acute Trypanosoma cruzi and Leishman- chronic inflammation seen in HIV-infected pa- ia infection, TGF-b production inhibits macro- tients. TGF-b produced in the mucosal lymph phage function, including IFN-g production nodes during HIV infection can also induce and increased pathogen replication (Silva et al. apoptosis of activated CD8þ T cells (Cumont 1991; Barral-Netto et al. 1992; Barral et al. et al. 2007), whereas promoting the generation 1993). Conversely, malaria infection leads to ac-

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tivation of latent TGF-b, whose production cor- Memorial Sloan Kettering Cancer Center Sup- relates with protective immune responses. This port Grant/Core Grant (P30 CA008748). The effect results in slowed parasite growth early on, Gladstone Institutes received support from a and less pathology late in infection (Omer and National Center for Research Resources Grant Riley 1998; Omer et al. 2003). TGF-b-mediated RR18928. induction of Treg-cell differentiation is also associated with higher rates of parasite growth after malaria infection in humans (Walther REFERENCES et al. 2005; Scholzen et al. 2009), and inhibiting Reference is also in this collection. TGF-b activity results in more robust CD8þ T- Acharya M, Mukhopadhyay S, Paidassi H, Jamil T, Chow C, cell responses and protection against reinfection Kissler S, Stuart LM, Hynes RO, Lacy-Hulbert A. 2010. av in mice (Ocana-Morgner et al. 2007). As hel- Integrin expression by DCs is required for Th17 cell dif- minth parasites stimulate TGF-b production ferentiation and development of experimental autoimmune encephalomyelitis in mice. J Clin Invest 120: 4445– and Treg-cell induction, they may, in fact, pro- 4452. tect the host from allergic diseases (Dittrich Alam R, Forsythe P,Stafford S, Fukuda Y. 1994. Transform- et al. 2008; Grainger et al. 2010). ing growth factor b abrogates the effects of hematopoie- tins on eosinophils and induces their apoptosis. J Exp Med 179: 1041–1045. CONCLUDING REMARKS Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ. 2007. Hepatitis C virus (HCV)- þ Studies in the past three decades have revealed specific CD8 cells produce transforming growth factor b that can suppress HCV-specific T-cell responses. J Virol the remarkably diverse and important functions 81: 5882–5892. of TGF-b in the immune system, and its pene- Allen JB, Manthey CL, Hand AR, Ohura K, Ellingsworth L, trating control of immune responses under Wahl SM. 1990. Rapid onset synovial inflammation and pathophysiological conditions. These discover- hyperplasia induced by transforming growth factor b. J Exp Med 171: 231–247. ies support the notion that immune regulatory Amarnath S, Dong L, Li J, Wu Y,Chen W.2007. Endogenous mechanisms, established by coopting cell sig- TGF-b activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected naling pathways that are evolutionarily con- þ 2 served, work in concert with mechanisms of human CD4 CD25 T cells. Retrovirology 4: 57. Arnold IC, Lee JY, Amieva MR, Roers A, Flavell RA, Spar- both innate and adaptive immune recognition wasser T,Muller A. 2011. Tolerance rather than immunity to ensure well-ordered immune activities. Fu- protects from Helicobacter pylori–induced gastric pre- ture investigations will define the precise cellu- neoplasia. Gastroenterology 140: 199–209. lar and molecular mechanisms of immune reg- Arruvito L, Sanz M, Banham AH, Fainboim L. 2007. Expan- sion of CD4þCD25þ and FOXP3þ regulatory T cells dur- ulation by TGF-b, and will explore targeting ing the follicular phase of the menstrual cycle: Implications this pleiotropic cell signaling pathway for ther- for human reproduction. J Immunol 178: 2572–2578. apies to treat pathogenic immune disorders. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, et al. 2011. Induction of colonic regulatory T cells by indige- nous Clostridium species. Science 331: 337–341. ACKNOWLEDGMENTS Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishi- Studies are supported by grants from the Na- kawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. 2013. Treg induction by a rationally selected mixture of tional Institute of Arthritis and Musculoskeletal Clostridia strains from the human microbiota. Nature and Skin Diseases (NIAMS) (RO1 AR060723 to 500: 232–236. M.O.L.), National Institute of Allergy and In- Balazovich KJ, Fernandez R, Hinkovska-Galcheva V, Su- fectious Diseases (NIAID) (RO1 AI122264 to chard SJ, Boxer LA. 1996. Transforming growth factor- b1 stimulates degranulation and oxidant release by ad- M.O.L. and R21 AI108953 to S.S.), the Rita Al- herent human neutrophils. J Leukoc Biol 60: 772–777. len Foundation (M.O.L.), Office of the Director Barral A, Barral-Netto M, Yong EC, Brownell CE, Twardzik (DP2 AI112244 to S.S.), UC Hellman Award DR, Reed SG. 1993. Transforming growth factor b as a virulence mechanism for Leishmania braziliensis. Proc (S.S.), and National Institutes of Health Natl Acad Sci 90: 3442–3446. (NIH) (T32-CA9149-35 to S.A.O.). Research Barral-Netto M, Barral A, Brownell CE, Skeiky YA, Ellings- in the Li laboratory is also supported by the worth LR, Twardzik DR, Reed SG. 1992. Transforming

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Regulation of Immunity by TGF-b

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Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Shomyseh Sanjabi, Soyoung A. Oh and Ming O. Li

Cold Spring Harb Perspect Biol published online January 20, 2017

Subject Collection The Biology of the TGF-β Family

TGF-β Family Signaling in Early Vertebrate TGF-β Family Signaling in Mesenchymal Development Differentiation Joseph Zinski, Benjamin Tajer and Mary C. Mullins Ingo Grafe, Stefanie Alexander, Jonathan R. Peterson, et al. Bone Morphogenetic Protein−Based Therapeutic TGF-β1 Signaling and Tissue Fibrosis Approaches Kevin K. Kim, Dean Sheppard and Harold A. Jonathan W. Lowery and Vicki Rosen Chapman TGF-β Family Signaling in Ductal Differentiation Bone Morphogenetic Proteins in Vascular and Branching Morphogenesis Homeostasis and Disease Kaoru Kahata, Varun Maturi and Aristidis Marie-José Goumans, An Zwijsen, Peter ten Dijke, Moustakas et al. TGF-β Signaling in Control of Cardiovascular TGF-β Family Signaling in Epithelial Function Differentiation and Epithelial−Mesenchymal Marie-José Goumans and Peter ten Dijke Transition Kaoru Kahata, Mahsa Shahidi Dadras and Aristidis Moustakas TGF-β Family Signaling in Tumor Suppression TGF-β Family Signaling in Connective Tissue and and Cancer Progression Skeletal Diseases Joan Seoane and Roger R. Gomis Elena Gallo MacFarlane, Julia Haupt, Harry C. Dietz, et al. Targeting TGF-β Signaling for Therapeutic Gain The TGF-β Family in the Reproductive Tract Rosemary J. Akhurst Diana Monsivais, Martin M. Matzuk and Stephanie A. Pangas Regulation of Hematopoiesis and Hematological TGF-β Family Signaling in Drosophila Disease by TGF- β Family Signaling Molecules Ambuj Upadhyay, Lindsay Moss-Taylor, Myung-Jun Kazuhito Naka and Atsushi Hirao Kim, et al.

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TGF-β Family Signaling in Neural and Neuronal Signaling Cross Talk between TGF-β/Smad and Differentiation, Development, and Function Other Signaling Pathways Emily A. Meyers and John A. Kessler Kunxin Luo

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