Lymphotoxin-Sensitive Microenvironments in Homeostasis and Inﬂammation

MINI REVIEW ARTICLE published: 31 July 2012 doi: 10.3389/ﬁmmu.2012.00243 Lymphotoxin-sensitive microenvironments in homeostasis and inﬂammation

Bryant Boulianne, Elisa A. Porﬁlio, Natalia Pikor and Jennifer L. Gommerman*

Department of Immunology, University of Toronto,Toronto, ON, Canada

Edited by: Stromal cell microenvironments within lymphoid tissues are designed to support immune Christopher G. Mueller, Centre cell homeostasis and to regulate ongoing immune responses to pathogens. Such stro- National de la Recherche Scientifique, France mal cell networks have been best characterized within lymphoid tissues including the spleen and peripheral lymph nodes, and systems for classifying stromal cell phenotypes Reviewed by: Burkhard Ludewig, Cantonal Hospital and functions are emerging. In response to inflammation, stromal cell networks within St. Gallen, Switzerland lymphoid tissues change in order to accommodate and regulate lymphocyte activation. Andrey Kruglov, German Rheumatism Local inflammation in non-lymphoid tissues can also induce de novo formation of lymphoid Research Center, Germany aggregates, which we term here “follicle-like structures.”Of note, the stromal cell networks *Correspondence: that underpin such follicles are not as well characterized and may be different depending Jennifer L. Gommerman, Department of Immunology, University of Toronto, on the anatomical site. However, one common element that is integral to the mainte- Toronto, ON, Canada M5S 1A8. nance of stromal cell environments, either in lymphoid tissue or in extra-lymphoid sites, e-mail: [email protected] is the constitutive regulation of stromal cell phenotype and/or function by the lymphotoxin (LT) pathway. Here we discuss how the LT pathway influences stromal cell environments both in homeostasis and in the context of inflammation in lymphoid and non-lymphoid tissues.

Keywords: lymphotoxin, follicular dendritic cell, ﬁbroblastic reticular cell, lymph node, chemokine, follicle-like structures

INTRODUCTION stromal cell environment can be re-established (Gommerman Within the secondary lymphoid tissues, stromal cell networks are et al., 2002). an integral scaffold for complex immune cell interactions nec- These findings have important implications for how we view essary to mount an effective immune response to pathogens. stromal cells. First, it suggests that stromal cells are highly The maintenance of the phenotype and function of some stro- dynamic and rely on continual input from LTαβ-expressing mal cell types is critically dependent on constitutive signaling cells. Second, since LTαβ is up-regulated on activated lympho- of the lymphotoxin-beta receptor (LTβR). LTβRisamemberof cytes (Summers-DeLuca et al., 2007), lymphocytes that have been the tumor necrosis factor (TNF) superfamily of receptors and is triggered by foreign or self-antigen (Ag) may have the poten- triggered by two ligands: membrane-bound LTα1β2 heterotrimers tial to provide stromal cell differentiation cues. Finally, the and LIGHT, resulting in the activation of both the canonical and ability to manipulate stromal cell biology via the LT pathway alternative NFκB pathways (Bista et al., 2010). During embryoge- allows one to study the potential function of LT-sensitive stromal nesis, the LTβR-dependent activation of NFκB within lymphoid cell types during tissue homeostasis and during inflammation. tissue organizer (LTo) cells is achieved by interaction with LTαβ- Here, we outline the role of LTβR signaling in the homeo- expressing lymphoid tissue inducer (LTi) cells, thus facilitating static maintenance of non-lymphoid cell types within LN and in lymph node (LN) and Peyer’s patched (PP) development (Mebius, the small intestine, and explore how LTβR signaling influences 2003; Ruddle and Akirav, 2009). changes in stromal cell phenotype/function during inflamma- In the adult animal, stromal cell phenotype and function tion within lymphoid tissues and in ectopic sites of follicle must be constitutively maintained for the lifetime of the host in development. order to maintain the integrity of lymphoid tissue, and much of this maintenance is accomplished by continual LTβR signal- LTβR-DEPENDENT REGULATION OF STROMAL CELLS ing (Gommerman and Browning, 2003). The cell types which IN PERIPHERAL LYMPHOID TISSUES provide LTαβ are generally lymphocytes, in particular B cells Lymph nodes are composed of a variety of stromal cell types whose (Tumanov et al., 2002, 2004), but can also be LTi-like innate lym- phenotype and function are being increasingly elucidated (Mal- phoid cells, especially in the context of the gut (Eberl, 2005). hotra et al., 2012). In general, marginal reticular cells are located in The moment such a homeostatic program is interrupted, as the sub-capsular sinus (SCS), under which follicular dendritic cells achieved by a single injection of the LT pathway antagonist (FDCs) populate the follicle. Fibroblastic reticular cells (FRCs) LTβR-Ig, stromal cell networks collapse and the lymphoid tis- are located in the T cell-rich paracortex area and LN medullary sues become disorganized (Mackay and Browning, 1998). When fibroblasts are found in the medullary cords. Vascular and lym- the drug is cleared, however, aspects of the lymphoid tissue phatic endothelial cells are an additional source of non-lymphoid

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FIGURE 1 | Stromal cell elements in the lymph node under lymphotoxin During inﬂammation, the LN becomes enlarged, stromal cells acquire new control during homeostasis and inﬂammation. The LT pathway is critical functions, and increased vascularization occurs (not depicted). In addition, for the proper maintenance and function of various stromal cell elements clusters of B and T cells aggregate within germinal centers during in the LN. During homeostasis, chemokine production by FDC in the T-dependent immune responses, and highly differentiated FDC within the GC primary follicle is required for B cell positioning (1). LTβR signaling in environment require LTβR signaling (3). To facilitate the output of plasma cells endothelial cells of HEV is also required for the expression of that emerge from these GC reactions, remodeling of the medullary region sulfotransferases that promote the proper glycosylation of PNAd (2). has been shown to occur (4).

cell types. In the context of the non-inflamed LN, we focus on activated B cells (Suzuki et al., 2010). Though the exact identity of FDCs, FRCs, and the endothelial cells that form high endothelial the FDC precursor is still unclear, it is thought that FDCs derive venules (HEV) since the role of the LT pathway in these cell types from mesenchymal cells in situ (Munoz-Fernandez et al., 2006; has been well described. Depicted in Figure 1 are examples of Allen and Cyster, 2008). It is well established that mature pri- LN stroma that are under LT control in both the steady state and mary FDCs are maintained within B cell follicles by virtue of the during inflammation. interaction between LTαβ on B cells and LTβR on a resident radioresistant stromal cell precursor (Fu et al., 1998; Gonzalez et al., FOLLICULAR DENDRITIC CELLS 1998; Endres et al., 1999). LTβR signals stimulate FDCs to secrete B cell follicles in lymphoid tissues are largely defined by FDC CXCL13, which attracts more B cells and induces them to up- (Allen and Cyster, 2008). FDCs are an important source of the B regulate LTαβ, thereby initiating a positive feedback loop (Ansel cell chemo-attractant CXCL13 which helps to establish the polar- et al., 2000). Constitutive signaling is required for FDC mainte- ity between B and T cell zones in lymphoid tissues. FDCs also nance and disruption of LTαβ-LTβR signaling in vivo results in the aid in germinal center responses by secreting the B cell survival rapid disappearance of FDCs along with a disorganization of the factor BAFF and by trapping immune complexes for display to BcellandTcellzones(Mackay et al., 1997).

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FIBROBLASTIC RETICULAR CELLS of expression of LTαβ on B cells (Tumanov et al., 2004). PP- Fibroblastic reticular cells are found predominantly in the T cell resident FDCs are somewhat different than LN FDCs in that they areas of LN (Balogh et al., 2008; Turley et al., 2010). FRCs secrete produce mediators that particularly encourage IgA class switch fibronectin, laminin, and ER-TR7 antigen, which bind ECM colla- recombination (Suzuki et al., 2010). Overarching the PP follicles gen fibers to produce a reticular network (Katakai et al., 2004). is the sub-epithelial dome that hosts a rich community of DC. This reticular network serves as a scaffold for cell migration Interestingly, expression of the chemokine CCL20 in the follicle- and retention (Bajenoff et al., 2006), provides a source of IL- associated epithelium which overlies the DC-rich sub-epithelial 7(Link et al., 2007), creates conduits that facilitate movement dome is also LT sensitive (Rumbo et al., 2004). The CCL20/CCR6 of chemokines and small soluble Ag (Roozendaal et al., 2009), axis may be important for the recruitment of B cells to the PP, and influences T cell tolerance in the steady state (Fletcher et al., and since B cells can express LTαβ, this could potentially drive 2011). Like FDCs, FRCs are thought to derive in situ from a the subsequent organization of the PP architecture (Williams, mesenchymal precursor, and multipotent mesenchymal stem cells 2006). Microfold (M) cells, which are also partially dependent isolated from human tonsils and bone marrow stimulated with on the LT pathway (Debard et al., 2001), are interspersed within recombinant TNFα and LTαβ develop an FRC phenotype in vitro the follicle-associated epithelium. Along with dome-resident DC, (Ame-Thomas et al., 2007). Murine FRCs cultured alone in vitro M cells play an important role in shuttling Ag from the gut lumen do not secrete ER-TR7 but upon co-culture with CD4+ Tcells into the PP for sampling and generation of immune responses. FRCs produce large amounts of reticula that are coated with In general, the stroma in PP is less well characterized than ER-TR7 in an LT- and TNFα-dependent manner (Katakai et al., in the LN. 2004). Similarly, LTβR-Ig treatment diminished FRC networks in Also within the small intestine are lymphoid tissue struc- pancreatic infiltrates of diabetic CXCL13-RIP mice in vivo (Link tures that develop strictly after birth called cryptopatches. In et al., 2011). However, it is unclear if the development and/or the presence of commensal bacteria, these cryptopatches mature maintenance of an intact ER-TR7-producing FRC network within to become isolated lymphoid follicles (ILF; Taylor and Williams, LN requires constitutive LTβR signaling, although the loss of 2005). LTαβ- and LTβR-deficient animals lack both ILF and cryp- T cells concomitant with a decrease in LTαβ is correlated with topatches. It is thought that IL-7 release by the underlying stroma FRC collapse in human immunodeficiency virus (HIV) infection in the small intestinal lamina propria induces the expression of (Zeng et al., 2012). LTαβ on LTi-like innate lymphoid cells. This in turn results in the triggering of LTβR to form the cryptopatch which matures HIGH ENDOTHELIAL VENULES into an ILF (Eberl, 2005). Like PP, ILF development also requires High endothelial venules are the portals of entry for naive lympho- the CCL20/CCR6 axis (Bouskra et al., 2008). Such ILF can be cytes into LN. This is because the endothelium of HEV displays an alternative location for the generation of mucosal IgA+ cells adhesion molecules, notably peripheral node addressin (PNAd). (Tsuji et al., 2008). Mice that receive LTβR-Ig treatment have hypo-cellular LN due to the requirement of LTβR signaling in regulating the expres- LTβR-DEPENDENT CHANGES IN LYMPHOID STROMAL sion of sulfotransferase enzymes that mediate post-translational CELLS DURING INFECTION AND INFLAMMATION modification of PNAd. Without these modifications, PNAd is + Several changes occur in the draining inflamed LN following expo- aberrantly expressed in HEV and naive L-selectin lymphocytes sure to Ag in adjuvant: systems for Ag transport are mobilized, transmigrate into LN tissues inefficiently (Browning et al., 2005). stromal cells acquire new functions, the LN becomes enlarged, A similar paradigm is observed for ectopic lymphoid aggregates neo-vascularization occurs to accommodate increased cellular in the pancreas (Drayton et al., 2003). Recently, it was shown input, and specialized niches that support T/B interactions are that dendritic cells (DC) are an important source of LTαβ in formed. In this section we describe these changes, how such providing the maturation signal for HEV. This suggests there changes are influenced by different types of stromal cells, and could be intimate cross-talk between DC and HEV (Moussion and the role of the LT pathway in orchestrating dynamic changes in Girard, 2011). Whether DC can communicate with other LTβR- the inflamed LN. expressing stromal cell elements within lymphoid tissues remains to be determined. ANTIGEN TRANSPORT Lymph-borne Ag enters LN into the SCS. There, Ag complexes LTβR-DEPENDENT REGULATION OF STROMAL CELLS are bound by CD169+F4/80− SCS macrophages (SCS Mϕ) that IN THE SMALL INTESTINE extend their processes into the SCS lumen to pick up Ag com- The LT pathway plays a critical role in regulation of IgA produc- plexes (Carrasco and Batista, 2007; Junt et al., 2007). Non-cognate tion in the gut (Kang et al., 2002), and this has been linked to the B cells subsequently pick up Ag complexes from SCS Mϕ, carry activity of LTβR signaling in gut-resident stromal cells in differ- them deeper into follicles, and deposit the Ag on FDCs in ger- ent types of gut-associated lymphoid tissues (Tsuji et al., 2008). minal centers (Phan et al., 2007). Interruption of this transport Such lymphoid tissues include PP, which are located along the chain results in early dissipation of germinal centers and impaired small intestine. PP contains large B cell follicles along with smaller affinity maturation. SCS Mϕ express LTβR and their presence in T cell regions in “inter-follicular” zones. Not unlike the case in the SCS region requires signals from LTαβ on B cells (Phan et al., LN, FDC and T/B segregation within the PP are likewise depen- 2009). As such, the expression of LTαβ on B cells is an important dentonLTβR signaling in PP stromal cells, primarily by virtue form of innate defense due to its ability to signal LTβRoncells

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within the SCS: the first point of Ag entry (Moseman et al., 2012). These structures have been observed in a wide variety of settings Stromal cells within the SCS have been described (Katakai et al., and display differing levels of organization, and in some cases have 2008), and it will be of interest to learn how these stromal cells been shown to support local immune responses (Aloisi and Pujol- interact with the Ag transport chain. Borrell, 2006). In this section, we review two examples of FLS and speculate on how the LT pathway may support such structures. LYMPHOID TISSUE REMODELING DURING INFLAMMATION AND INFECTION INDUCIBLE BRONCHIAL LYMPHOID TISSUE Dramatic changes occur in lymphoid tissues in response to viral Inducible bronchus-associated lymphoid tissues (iBALT; Randall, infections. For example, during lymphocytic choriomeningitis 2010) are FLS that form in the lungs in response to respira- virus (LCMV) infection, lymphoid tissue architecture becomes tory inflammation due to infection (Moyron-Quiroz et al., 2004; disorganized but is eventually restored in a manner that depends Lugade et al., 2011), chronic inflammation (Hogg et al., 2004), or on LTαβ expression on LTi-like innate lymphoid cells (Scandella autoimmunity (Rangel-Moreno et al., 2006). The content of such et al., 2008). In addition to this dramatic remodeling, lymphoid structures varies from highly organized niches beneath a dome stroma can be an important source of type I interferons dur- epithelium with defined T cell and B cell areas and FDC capable ing viral infection, and LTβR signaling in splenic stroma can of supporting germinal centers, to small clusters of lympho- drive such a Type I interferon response independent of MyD88 cytes containing mostly B cells and some FDC (Moyron-Quiroz or TRIF-derived signals (Schneider et al., 2008). et al., 2004). Local production of CXCL13, CCL19, and CCL21 In the LN, inflammation also greatly increases the size of the LN drives the recruitment of lymphocytes to iBALT follicles (Foo and this LN hypertrophy is accompanied by endothelial cell pro- and Phipps, 2010). Fully formed iBALT require approximately liferation that can be promoted by the production of VEGF. FRC 10 days to become organized niches in adult mice post-infection is a source of VEGF and this is dependent on LTαβ/LTβR signaling (Moyron-Quiroz et al., 2004; Halle et al., 2009) but are maintained (Chyou et al., 2008) as well as input by the alternative LTβR ligand for months (Moyron-Quiroz et al., 2006). LIGHT (Zhu et al., 2011). Furthermore, LTαβ expression on B cells Unlike LN and PP which require LTαβ–LTβR signaling for can also drive HEV network extension/remodeling in response to their formation, studies using LTα−/− mice have shown that LCMV infection independent of VEGF (Kumar et al., 2010). Thus, LTβR signaling is not required for iBALT formation or induc- through various mechanisms, the LT pathway is important for tion of CXCL13, CCL19, and CCL21 during acute inflammation accommodating the increased flow of lymphocytes into a draining (Moyron-Quiroz et al., 2004). Instead, Randall and colleagues reactive LN. The medullary stroma, which supports lymphocyte determined that CD4+IL-17+ cells are necessary to initiate iBALT egress from the LN, also becomes remodeled during an immune formation (Moyron-Quiroz et al., 2004). However, once estab- response. This may be important for providing a niche for the lished, CD4+IL-17+ cells are insufficient for optimal organization incredible burst in plasma cell output that is generated follow- and maintenance of iBALT which instead is dependent on LTβR ing a germinal center response. In this process, collagen-poor and signaling. collagen-rich areas are created, with plasma cells settling in the collagen-rich regions, presumably to take advantage of stromal FLS IN THE CENTRAL NERVOUS SYSTEM cell factors that may enhance their survival (Zhu et al., 2011). Follicle-like structures have been documented at sites of chronic inflammation in several autoimmune diseases including: rheuma- GERMINAL CENTER FORMATION toid arthritis, Sjörgen’s syndrome, systemic lupus erythematosus, As mentioned, mature primary FDCs are located throughout B and Multiple Sclerosis (MS; Aloisi and Pujol-Borrell, 2006). There cell follicles and rely on constitutive, low-level LTβR signaling is a range in the level of lymphoid-like organization of these (Fu et al., 1998; Gonzalez et al., 1998; Endres et al., 1999). Dur- structures: from perivascular infiltrates, to diffuse aggregates with ing an immune response, activated Ag-specific B cells that receive HEV-like vessels, to organized follicles with T and B cell segrega- co-stimulation from T cells up-regulate LTαβ even further and tion and underlying FDC networks (Browning, 2008). The disease provide stronger LTβR signals to FDCs (Vu et al., 2008). This ele- relevance of FLS is associated with local tissue injury and cell death. vated LTβR signaling prompts FDCs to mature into secondary In MS, FLS preferentially accumulate in the meninges in patients FDCs within germinal centers. Secondary FDCs up-regulate com- at the later progressive stage of the disease (Serafini et al., 2004), plement receptors CD21 and CD35 as well as FcγRIIB to enhance and meningeal FLS are associated with increased demyelination capture of Ag complexes (Allen and Cyster, 2008). While the exact and neuronal loss (Magliozzi et al., 2007, 2010). role for Ag complexes on FDCs is still debated, it is likely that they A role for the LT pathway in attenuating clinical disease has help sustain the germinal center response and enhance affinity previously been described in the rodent model of MS, experi- maturation. Secondary FDCs also begin to express FDC-M1 anti- mental autoimmune encephalomyelitis (EAE; Gommerman et al., gen (Mfg-e8), which may play a role in the clearance of apoptotic 2003). Pharmacological disruption of LT signaling reduces the germinal center B cells (Kranich et al., 2008). size and number of meningeal FLS compared with control treatment (Columba-Cabezas et al., 2006). Impaired FLS formation INFLUENCE OF LTβR SIGNALING ON ECTOPIC following LT inhibition is concomitant with reduced mRNA levels LYMPHOID TISSUE of CXCL10 and CXCL13 in the brain, suggesting that LT regu- Inflammation in peripheral tissues can create an environment that lates chemokine induction at peripheral sights of inflammation. is permissive to the formation of follicle-like structures (FLS). However, not unlike iBALT, emerging studies in EAE also support

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the notion that distinct pathways may culminate in orchestrat- with other forms of input, such as Th17 cells, to orchestrate distinct ing FLS. For example, adoptively transferred myelin-specific Th17 stages of FLS formation (i.e., initiation versus maintenance), and cells induce EAE concomitant with FLS formation (Peters et al., which LTαβ and LTβR-expressing cell types support FLS. Indeed, 2011). How signals from the LT pathway and from Th17 cells co- while exciting advances have been made toward understanding integrate to induce and/or maintain FLS structures in the CNS is the nature of stromal cell types in peripheral LN, this question has unknown. barely been addressed in the mucosal lymphoid tissues and in the context of FLS. Unraveling the many facets of LTβR signaling in CONCLUSION regulating and fine-tuning the immune response is a tall order, but It is clear that LTβR-generated signaling underpins the mainte- of value for considering the therapeutic potential of LT inhibitors nance and in some cases the function of stromal cell types within in treatment of chronic diseases. lymphoid tissues. Not discussed here are examples of how LTβR signaling is also important in myeloid/DC biology (Deluca and ACKNOWLEDGMENTS Gommerman, 2012), and DC have been implicated in regulat- The authors wish to acknowledge the support of the MS Soci- ing stromal cells and the formation of FLS (GeurtsvanKessel et al., ety of Canada for a studentship awarded to Natalia Pikor and for 2009; Halle et al., 2009; Moussion and Girard, 2011). Thus, it will an operating grant to Jennifer L. Gommerman. We also wish to be of interest to learn more about the connections between DC and acknowledge the Canadian Institutes of Health Research for an stromal cells with respect to the LTpathway. Moreover, many ques- operating grant to Jennifer L. Gommerman (MOP # 89783) and tions remain unanswered regarding how the LTpathway integrates studentships for Elisa A. Porfilio and Bryant Boulianne.

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B cells are dispensable for main- center reaction. J. Immunol. 180, regulates inflamed draining lymph Lymphotoxin-sensitive microenviron- tenance of the follicle-associated 2284–2293. node hypertrophy. J. Immunol. 186, ments in homeostasis and inflammation. epithelium but are required for devel- Williams, I. R. (2006). CCR6 and 7156–7163. Front. Immun. 3:243. doi: 10.3389/ opment of lymphoid follicles in the CCL20: partners in intestinal immu- fimmu.2012.00243 Peyer’s patches. J. Immunol. 173, nity and lymphorganogenesis. Ann. This article was submitted to Frontiers 86–91. N. Y. Acad. Sci. 1072, 52–61. in Antigen Presenting Cell Biology, a Turley, S. J., Fletcher, A. L., and Elpek, Zeng, M., Paiardini, M., Engram, J. Conflict of Interest Statement: The specialty of Frontiers in Immunology. K. G. (2010). The stromal and C., Beilman, G. J., Chipman, J. G., authors declare that the research was Copyright © 2012 Boulianne, Porfilio, haematopoietic antigen-presenting Schacker, T. W., Silvestri, G., and conducted in the absence of any com- Pikor and Gommerman. This is an open- cells that reside in secondary lym- Haase, A. T. (2012). Critical role mercial or financial relationships that access article distributed under the terms phoid organs. Nat. Rev. Immunol. 10, for CD4 T cells in maintaining lym- could be construed as a potential con- of the Creative Commons Attribution 813–825. phoid tissue structure for immune flict of interest. License, which permits use, distribution Vu, F., Dianzani, U., Ware, C. F., Mak, T., cell homeostasis and reconstitution. and reproduction in other forums, pro- and Gommerman, J. L. (2008). ICOS, Blood. doi: 10.1182/blood-2012-03- Received: 08 June 2012; accepted: 18 July vided the original authors and source CD40, and lymphotoxin beta recep- 418624 [Epub ahead of print]. 2012; published online: 31 July 2012. are credited and subject to any copy- tors signal sequentially and inter- Zhu, M., Yang, Y., Wang, Y., Wang, Citation: Boulianne B, Porfilio EA, right notices concerning any third-party dependently to initiate a germinal Z., and Fu, Y. X. (2011). LIGHT Pikor N and Gommerman JL (2012) graphics etc.

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