Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm

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Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm Aakanksha Jain and Chandrashekhar Pasare This information is current as J Immunol 2017; 198:3791-3800; ; of September 24, 2021. doi: 10.4049/jimmunol.1602000 http://www.jimmunol.org/content/198/10/3791 Downloaded from References This article cites 150 articles, 51 of which you can access for free at: http://www.jimmunol.org/content/198/10/3791.full#ref-list-1

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Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm Aakanksha Jain and Chandrashekhar Pasare Activation of cells in the adaptive immune system is a The third signal consists of innate cytokines that are pro- highly orchestrated process dictated by multiples cues duced as a result of PRR activation (3). The cytokine milieu from the innate immune system. Although the funda- helps T cells differentiate into protective T cell subsets re- mental principles of innate control of adaptive immu- quired for host immunity against a given pathogen (7, 8). The nity are well established, it is not fully understood how three-signal model described a fundamental link between the innate cells integrate qualitative pathogenic information innate and adaptive immune systems and defined the re- to generate tailored protective adaptive immune requirements for inducing a measurable T cell response, here- sponses. In this review, we discuss complexities involved after referred to as “productive immunity.” Downloaded from in the innate control of adaptive immunity that extend The requirement of the concurrent presence of all three beyond TCR engagement, costimulation, and priming signals ensures diverse, but selective, T cell activation. A basic cytokine production but are critical for the generation of understanding of these signals has helped us design immu- nogenic Ags that are able to induce productive immunity. protective T cell immunity. The Journal of Immunology, However, translating immunogenicity to protective immunity 2017, 198: 3791–3800. continues to be a challenge (9). So far, most successful vaccines http://www.jimmunol.org/ rely on generating B cell responses that result in neutralizing cells and B cells are equipped with a diverse repertoire Abs against a given pathogen (10); there has been limited of receptors that are capable of recognizing a vast array success in defining and inducing protective pathogen-specific T of Ags. This diversity allows for protection against T cell immunity. This is largely due to the fact that the three- constantly evolving pathogens but also gives rise to substantial signal model mentioned above is a vast oversimplification of self-reactivity. Avoiding self-reactivity while maintaining clonal innate control of adaptive immunity. In addition to the three diversity is an intriguing evolutionary design problem. A sem- broad information routes, innate cells provide subtle infor-

inal leap in our understanding of the activation of the adaptive mation about the pathogen to the adaptive immune system, by guest on September 24, 2021 immunesystemwasduetothelateCharlesJaneway,Jr.He which facilitates protective T cell responses. Experimental proposed that innate cells should be equipped with germline- settings often limit important host–pathogen-associated vari- encoded pattern recognition receptors (PRRs) to recognize ables by using purified ligands, model Ags, unnatural routes “nonself” conserved microbial components, also referred to as of infections, and purified cell types. Although a reductionist pathogen-associated molecular patterns (PAMPs) (1). Activated approach is essential to gain mechanistic insights into a innate immune cells would then convey the information about pathway, such isolated challenges are never presented to the the nature and origin of the Ag to the adaptive immune cells to host during a natural infection. Microorganisms carry ligands mount an appropriate adaptive immune response. This idea for multiple PRRs and activate various cells types during the formed the basis for the now-established three-signal paradigm course of an infection. History of prior infection or presence of innate control of adaptive immunity (2, 3) (Fig. 1A). The first of coinfection can further complicate the process of innate signal provided by innate cells is the presentation of the antigenic activation (11, 12). Also, it has become increasingly clear that peptide, which is necessary for activation of the TCR and clonal the route of infection and the priming microenvironment expansion of Ag-specific T cells. Because the peptide can be of have an enormous effect on T cell differentiation (13). self or nonself origin, Ag presentation alone is unable to provide Depending on the class of pathogen, innate cells also produce any qualitative information about the source of the Ag (4). The the IL-1 family of cytokines (14) and/or type I IFNs (15) that second signal is provided via costimulatory molecules that are further modulate T cell function. Even after T cell differen- upregulated on APCs only when the Ag is associated with a tiation, the presence of innate cytokines in the surrounding PAMP (5, 6). Thus, costimulation is necessary for self versus environment maintains the T cells in a fairly plastic state, nonself distinction. suggesting a persistent interaction between the innate and

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Address correspondence and reprint requests to Dr. Chandrashekhar Pasare, UT South- TX 75390-9093 western Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: [email protected] ORCID: 0000-0002-8142-2488 (C.P.). Abbreviations used in this article: DC, dendritic cell; IFNAR, IFN-a/b receptor; LCMV, Received for publication December 6, 2016. Accepted for publication March 2, 2017. lymphocytic choriomeningitis virus; PAMP, pathogen-associated molecular pattern; PRR, This work was supported by National Institutes of Health Grants AI123176, AI113125, pattern recognition receptor; SCFA, short-chain fatty acid; Treg, regulatory T cell. and AI115420 (to C.P.). Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1602000 3792 BRIEF REVIEWS: INNATE CUES FOR ADAPTIVE IMMUNITY adaptive immune systems (16). In summary, innate control was shown to enhance cross-presentation in an IFN-a/b receptor of adaptive immunity is a complex process of information (IFNAR)-dependent manner (34). Type I IFN–treated human transfer that extends beyond the three-signal paradigm DCs showed delayed degradation of internalized Ag that (Fig. 1B). Although fully elucidating such complexities will enhanced their capacity to cross-present Ags and promote continue to be a challenge, in this article we discuss exam- CD8 T cell activation. These studies highlight the ability of ples of context-dependent innate activation that regulate the innate immune system to convey qualitative information and fine-tune T cell immunity to a far greater extent than about the cargo to the adaptive immune system by dictating previously appreciated. how the cargo is handled and presented. Thus, a cell’s decision to present peptides on either MHC class I or MHC class II Context-dependent role of PRRs in shaping adaptive immunity molecules is not merely a reflection of the origin of the Ag but The discovery of various classes of PRRs and identifica- also a consequence of the complex interplay between the PRRs tion of their microbial ligands has led to a detailed under- that are engaged. Although advantageous for pathogen- standing of innate immune recognition (15, 17, 18). PRRs specific immunity, this mechanism also exposes the host to are strategically located in subcellular compartments based manipulations by the microbes. For instance, certain viruses have onthenatureoftheirligandsthatactivateuniquesignal- the ability to engage plasma membrane TLRs (35, 36) that can transduction programs necessary for host defense (19). A potentially suppress antiviral CD8 T cell activation. Alternatively, detailed description of specific PRRs and their signal- bacteria can mask their TLR-activating PAMPs (37), thereby transduction pathways can be found in other reviews (18–20). enhancing cross-presentation and the generation of CD8 T cells Downloaded from In this article, we focus on how activation of individual or that can cause immunopathology and tissue destruction, multiple PRRs can affect Ag presentation and, in turn, facilitating bacterial dissemination. adaptive immunity. In addition to regulating Ag presentation, PRR activation Regulation of Ag presentation by PRR signaling. Although each leads to induction of costimulatory molecules that are necessary class of PRR induces distinct innate responses, the activation of for T cell activation (5, 6). One of the most well-studied co- adaptive immunity depends on their ability to induce dendritic stimulatory interactions is that of CD80/86 with CD28 http://www.jimmunol.org/ cell (DC) maturation (5, 6). Following PRR activation, DCs expressed on T cells. CD28 signaling lowers the threshold for upregulate MHC and costimulatory molecules and migrate to TCR activation and leads to transcription of proliferative genes the draining lymph nodes to interact with naive T cells that and IL-2 production (38). In addition, there are various TNFR are specific to the microbial Ag (21). DCs process and present superfamily members that serve as costimulatory molecules. extracellular and endosomal peptides on MHC class II molecules Several TNFR family members, such as OX40, 4-1BB, and to activate CD4 T cells, whereas peptides derived from cytosolic CD27, have the ability to promote effector functions of specific proteins are presented on MHC class I to activate CD8 T cells T cell subsets (39, 40). In addition, differential Notch ligand

(22). Some specialized DCs also have the unique capability expression by DCs has been implicated in differential priming by guest on September 24, 2021 to take up and present exogenous peptides onto MHC class I of T cells (41), and Notch signaling is reported to be important through the process of cross-presentation (23, 24). This enables for activation and effector function of CD4 T cells (42). It DCs to activate CD8 T cells against tumors or viruses that did not remains to be examined whether specific PRRs control adaptive infect the DCs directly. One of the first steps by which the innate immunity by influencing expression of a particular set of co- immune receptors affect adaptive immunity is by influencing the stimulatory molecules on DCs. It is also unclear how T cells handling of endocytic and phagocytic cargo. Activation of PRRs, integrate diverse costimulatory signals to mount a protective especially TLRs, was shown to accelerate endocytosis and response. A substantial amount of work has been done in phagocytosis, thus affecting Ag processing and presentation (19, understanding the role of specific costimulatory molecules in 25, 26). However, recent studies shed light on how activation of T cell functions; therefore, we refer readers to those reviews certain TLRs can also dictate cargo handling following uptake (40, 43–45) for information on how various costimulatory (27–29). Although activation of surface TLR4 transiently molecules affect adaptive immunity. enhances cross-presentation (30), phagosome-intrinsic TLR PRR cross-talk: synergy and cross-inhibition. Although individ- signaling provides self versus nonself identity of the cargo and ual PRRs have significant immune-modulatory capabilities, promotes MHC class II presentation and CD4 T cell activation protective host responses are often dependent on the ability (31, 32). It was recently shown that activation of TLR4 and of the innate immune system to simultaneously engage TLR2 leads to upregulation of transcription factor EB, which multiple PRRs. TLR3 and TLR4 synergize with TLR7, drives rapid degradation of phagosomal content and prevents its TLR8, and TLR9 to enhance the production of IL-12 and cross-presentation on MHC class I molecules, thus enhancing IL-23, as well as the Th1-driving capacity of DCs (46). antigenic peptide loading on MHC class II molecules (33). This Cooperation between PRRs was shown to result in unique suggests that a predominant CD4Tcellresponseisgenerated transcriptional changes that control the quality, quantity, and in response to extracellular bacterial pathogens. Conversely, kinetics of chemokine and cytokine production (47). One very TLR9 stimulation does not induce transcription factor EB well-known example of such PRR synergy is inflammasome expression, which protects cargo from degradation and makes activation by virulent pathogens. Sequential (48) or simul- it available for cross-presentation through the cytosolic route or taneous (49) activation of TLRs and NLRs leads to the by capturing the cargo into recycling endosomes (33). Because production of bioactive IL-1b and IL-18, which influence TLR9 is likely activated by viral DNA following phagocytosis T cell immunity, as discussed later. Similarly, activation of of an infected cell, this process ensures the generation of dectin-1 was shown to be important for TLR-induced effective CD8 T cell responses to eliminate viral infections. reactive oxygen species production (50) that can lead to Activation of TLR3, TLR7, and TLR9 by nucleic acids also inflammasome activation (51,52)andIL-1production, The Journal of Immunology 3793 thereby promoting antifungal Th17 responses. Moreover, Unlike IL-6, IL-12, or IL-4, IL-1 family members and type I the consequence of PRR cross-talk is also determined by IFN cytokines are largely produced as a result of cytosolic the innate cell type. Zymosan-mediated coactivation of invasion by virulent pathogens or extensive tissue damage, with dectin-1 and TLR2 enhances IL-12 and TNF-a production certain exceptions, such as cytosolic sensing of LPS (58, 59) in bone marrow–derived macrophages (50), whereas, in bone or mRNA from pathogenic and nonpathogenic bacteria marrow–derived DCs, dectin-1 suppressed TLR2-dependent (60–64). Hence, they are secreted in a much more rapid fashion IL-12 (53). Dectin-mediated modulation of IL-12, IL-6, and than priming cytokines. IL-1a and IL-33 can be rapidly re- IL-23 production can promote Th17 differentiation at the leased upon the death of necrotic cells (65, 66), whereas IL-1 expense of Th1 differentiation. These examples underscore and IL-18 are present in a premade pro-form in certain cell the importance of coincident activation of PRRs and suggest types and can be acutely secreted via rapid inflammasome that, although individual PRRs can operate in isolation, their activation (49). In contrast, type I IFNs rely on IRF3- and cooperation is important to generate an optimal adaptive IRF7-mediated signaling. Plasmacytoid DCs can rapidly immune response. In addition to synergistic cross-talk secrete type I IFNs because they exhibit higher baseline ex- between PRRs, there are examples of cross-inhibition. pression of IRF3 and IRF7 (67). The nature of the cellular Negative cross-talk, which might have evolved to prevent source of IL-1 family members and type I IFNs also differs immunopathology, can sometimes result in exacerbation of from cells that produce priming cytokines to modulate T cell infection. While isolated activation of endosomal TLRs activity. Recent reports show that nonimmune cells can also promotes CD8 T cell priming, simultaneous engagement provide IL-1–related cytokines to promote effector function Downloaded from of surface and endosomal TLRs inhibits CD8 T cell expansion of tissue-resident T cells (68, 69). Also, in addition to plas- (54). The dominant effect of surface TLRs might be a con- macytoid DCs, every nucleated cell in the body has the ca- sequence of preferential recruitment of myeloid DCs that are pacity to produce type I IFNs in response to viral infections. incompetent in inducing CD8 T cell priming and leads to However, T cell–priming cytokines are understandably CD4-biased responses (54). This is particularly relevant in produced by professional APCs, such as DCs, and inflamma- the case of viral–bacterial coinfections and provides a potential tory cells, such as monocyte-derived DCs and macrophages. http://www.jimmunol.org/ mechanism for how bacterial infections suppress antiviral Therefore, it is likely that, whereas the priming cytokines immunity. Similarly, peptidoglycan-mediated activation of NLRs dictate T cell differentiation in the secondary lymphoid or- in DCs in vitro inhibited Ag cross-presentation induced by TLR4 gans, the IL-1 and type I IFN family of cytokines operate in activation (55). Another instance of a contextual outcome of PRR the periphery to imprint further differentiation for tissue- cross-talk is the engagement of the Mincle receptor, a C-type lectin specific effector function. Below, we discuss how each of that can act as an inhibitory or activating receptor, based on the these families has a distinct, as well as context-specific, role nature of the pathogen. Activation of Mincle by Leishmania in dictating the magnitude and quality of T cell responses. suppresses DC maturation and IL-12 production, likely by Innate cytokines for T cell priming. Distinct differentiation states by guest on September 24, 2021 negatively regulating inflammatory signaling through other PRRs of CD4 T cells are traditionally defined by the lineage-specific (56). Hence, deletion of Mincle receptor resulted in improved Th1 transcription factors and their effector cytokines. Unique T cell differentiation. However, Mycobacterium induces IL-6 production subsets are largely shaped by the innate cytokines presented by macrophages in a Mincle-dependent manner, which results in during priming. In brief, IL-12 promotes Th1 differ- reduced Th17 responses in Mincle-deficient mice (57). These entiation by driving T-bet expression (70). IL-4 drives Th2 examples illustrate the importance of studying PRR cross-talk differentiation in both a paracrine and autocrine manner using PAMPs associated with the pathogen in their native form, (71–74). The combination of IL-6 and TGF-b promotes to reveal their true impact on host immunity. Collectively, these Th17 differentiation (75). IL-6 and TGF-b can synergize studies highlight the extensive intra- and intercellular PRR with IL-23 and IL-1 to further stabilize the Th17 program cross-talk that takes place during infections and its consequential (76). In the absence of an infection, TGF-b produced by effects on the quality of T cell responses. migratory DCs induces regulatory T cells (Tregs) that are critical for maintaining peripheral tolerance (77). We refer Complexity of cytokine cues: diverse but customized our readers to other reviews for detailed information on the In addition to Ag presentation and costimulation, the third role of individual priming cytokines (7). We will limit our signal that shapes the quality of T cell responses is the pro- discussion to the context-dependent roles of innate cytokines duction of innate cytokines. NF-kB–dependent cytokines, in T cell differentiation. T cell subsets are often studied such as IL-12, IL-6, and TNF-a (20), drive acute inflam- using in vitro systems through the use of defined priming mation and dictate T cell differentiation. Two other major cytokine cocktails that result in highly polarized T cell classes of innate cytokines, IL-1 family and type I IFNs, often populations. However, during a real infection, activated DCs cooperate with priming cytokines in the generation of pro- generate a complex milieu of innate cytokines, leading to the tective T cell immunity. Both immune and nonimmune cells priming of a heterogeneous CD4 T cell population. Therefore, can produce the IL-1 family of cytokines (IL-1a, IL-1b, in vitro–polarized T cells might not represent physiological IL-18, and IL-33) as an outcome of recognition of virulence differentiation processes that give rise to a diverse effector factors, cellular stress, or cell death. In contrast, type I IFNs population in vivo. Recent studies using whole-pathogen lysates are produced following activation of nucleic acid sensors in and live microbes have begun to unravel the complexities of the endosomes (TLR3, TLR7/8, and TLR9) or in the cytosol cytokine requirements for T cell differentiation. Priming naive (RLRs and cGAS) (15). The IL-1 family of cytokines and type human CD4 T cells using whole-pathogen lysates revealed I IFNs drive systemic immune responses by inducing an qualitatively distinct patterns of cytokine production between acute-phase response and a global antiviral state, respectively. Th17 populations induced by Staphylococcus aureus and 3794 BRIEF REVIEWS: INNATE CUES FOR ADAPTIVE IMMUNITY

Candida albicans(78).S. aureus–induced Th17 cells secrete death, which can potentially compromise Ag presentation and IL-17, as well as IL-10, independent of IL-1b stimulation, the generation of T cell immunity. Over the years, many whereas C. albicans–specific Th17 cells produce IL-17 and inflammasome-independent pathways involving caspase-8 and IFN-g, requiring IL-1b in addition to IL-6 and IL-23. neutrophil-derived serine proteases have also been reported for Furthermore, a mouse model of Citrobacter rodentium IL-1 maturational cleavage (95, 96). Although there is lack of infection showed that IL-22–producing T cells, dependent on evidence, it is tantalizing to hypothesize that, although the IL-23 for differentiation, were required for protection (79). inflammasome-dependent IL-1b drives systemic inflammation, These cells expressed RORgt, the master transcriptional inflammasome-independent mechanisms of IL-1 production regulator of the Th17 lineage, but failed to produce IL-17. have evolved for much subtler functions, such as influencing In the context of experimental autoimmune encephalomyelitis, T cell biology during priming, as well as reactivation. IL-23 was alternatively shown to induce “pathogenic Th17” Type I IFNs in adaptive immunity. Type I IFNs are proin- cells, which produce IFN-g and GM-CSF in addition to flammatory cytokines that are produced in response to viral IL-17 (80). In agreement with these studies, transcriptomic infections. In the absence of TCR signaling, type I IFNs trigger analysis showed variable gene-expression profiles within the a proapoptotic program, potentially to prevent bystander T cell Th17 population (81). Collectively, these findings suggest that, activation (97). However, direct activation of IFNAR can act depending on the immune challenge, naive T cells get exposed to as a costimulatory signal when engaged in sync with TCR a unique innate cytokine milieu that drives functionally peculiar (97). In fact, activation of IFNAR signaling on CD8 T cells T cell subpopulations, even though they may belong to the same was shown to bypass the requirement of CD4 T cell help for Downloaded from umbrella lineage. Studying functional T cell subsets based on the CD8 immunity during LCMV infection (98). IFN-a innate cytokine stimulation that drove their differentiation, synergizes with IL-12 to provide signal 3 during activation rather than their narrow effector cytokine profile, will likely of naive, as well as Ag-experienced, CD8 T cells for their clonal reveal more valuable information regarding the generation of expansion and effector function (99–101). IFN-a/b can act protective T cell responses against specific pathogens. together with IL-12 to enhance Th1 and CD8 T cell immunity IL-1 family of cytokines in T cell immunity. Priming cytokines, (102, 103). IFN-a enhances IL-12 and IL-18 responsiveness by http://www.jimmunol.org/ like IL-6, IL-12, and IL-4, often synergize with the IL-1 family increasing IL-18RA expression on T cells (104). While promoting of cytokines for generation of protective immunity. Although Th1 bias in human T cells, type I IFNs also actively suppress Th2 the exact role of each IL-1 family member in regulating T cell cell function (105–107). Interestingly, the nature of the responses is not clear, there is substantial evidence that IL-1b, pathogen appears to dictate the requirement of type I IFNs IL-18, and IL-33 contribute to Th17, Th1, and Th2 CD4 for adaptive immunity. Lack of T cell–intrinsic IFNAR T cell responses, respectively (82). A series of studies verified signaling resulted in compromised CD8 T cell expansion and the importance of IL-1 in Th17 cell biology (83–86). T cell– memory formation following LCMV infection, whereas vaccinia intrinsic IL-1R signaling was shown to promote pathogenicity virus–specific, vesicular stomatitis virus–specific, and Listeria by guest on September 24, 2021 of Th17 cells by synergizing with IL-6 and IL-23 (87). IL-18 monocytogenes–specific CD8 T cell expansion was independent has been implicated in Th1 and CD8 T cell function. The of type I IFN–mediated signaling (108). This differential combination of IL-12 and IL-18 induces IFN-g production requirement extends to CD4 T cells as well, where type I by memory CD8 T cells and Th1 cells, independent of TCR IFNs were critical for CD4 T cell expansion following LCMV, activation (88, 89). IL-18 can also enhance T-bet expression but not L. monocytogenes, infection (109). Because type I IFNs in human CD4 T cells, thus promoting Th1 function (90). are emerging as an attractive choice for vaccine adjuvants, these IL-33 is produced as an alarmin when cells undergo studies suggest that we need to be conscious of their differential inflammatory cell death (66). The adaptive function of pathogen-specific impact on T cell immunity for successful vac- IL-33R signaling was first discovered in the context of type cine design (110). 2 immunity, because this receptor was prominently expressed In summary, PRR activation results in the production of a on Th2 cells (91). Recently, it was found that colonic (92), functionally distinct set of innate cytokines that are crucial for adipose tissue–resident (69), and muscle (68) Tregs also T cell differentiation and function. Priming cytokines trigger express high levels of IL-33R (ST2). IL-33R signaling transcriptional programs for lineage differentiation, and the promotes proliferation and maintenance of induced Tregs, IL-1 family of cytokines and/or the type I IFN family cooperate a novel mechanism of IL-33–dependent suppression of with priming cytokines to dictate the final outcome of effector inflammation (69, 92). IL-33R–deficient mice also show differentiation. Interestingly, there seems to be spatial and higher viral burden during lymphocytic choriomeningitis temporal distinctions in how various innate cytokines con- virus (LCMV) infection, which was recently attributed to tribute to T cell immunity. Moreover, pathogens often dictate Th1-intrinsic (93) and CD8 T cell–intrinsic (94) IL-33R the set of innate cytokines required for protective T cell im- signaling. These studies emphasize the multifaceted nature munity (109, 111). Therefore, it is crucial to be able to induce of the IL-1 family of cytokines and show that they can act specific combinations of innate cytokines with appropriate as mediators of acute inflammation during host invasion, as kinetics and tissue distribution to harness the innate immune well as drivers of homeostatic adaptive immunity in the system for the generation of long-term pathogen-specific steady-state. T cell immunity. IL-1 and its relatives are produced under strict regulation, likely as a result of their highly inflammatory nature. Inflam- Effects of systemic and local immune status on T cell priming masome activation is a major mechanism for the production Different anatomical tissues are exposed to distinct microbial of bioactive IL-1b. It is important to note that a major con- and environmental challenges. To prevent immunopathology, sequence of inflammasome activation is pyroptotic cell not every infection experiences the full potential of the immune The Journal of Immunology 3795 system. Instead, the intensity of the T cell response is likely to examined whether these DCs have dedicated receptors or other be modulated by the local, as well as the systemic, immune sensory mechanisms that alert them to the presence of an al- status of the host. Infection at the barrier tissues, such as the lergen or helminth infection. skin or gut, presents a moderate risk to the host. Therefore, the Recent studies identified a tissue-resident memory T cell immune response is often contained in the tissue and, in some population that serves as the front-line defense against rein- cases, even leads to tolerance. In contrast, systemic infection fections (122–125). Specific DC populations have now been (bacteremia or viremia) is treated as an immediate threat and identified that preferentially generate tissue-resident T cells triggers a systemic inflammatory response. Previous infections (126, 127). These findings present us with an exciting opin the host, even after resolution, can further alter the immune portunity to induce tissue-specific immunity by individually response to new infections. Therefore, the anatomical location targeting relevant DC subsets. of the infection and host immune status are critical deter- Global immune status and history of infection. Infection models in minants of protective immunity. mice often ignore the impact of prior infections. However, in Priming microenvironment. Most of our understanding of the reality, no one is absolutely naive to microbial challenge; immune system is derived from studies done in secondary concurrent or past infections can affect the host response to lymphoid organs, such as the spleen or lymph nodes. However, unrelated pathogens. History of infection or ongoing patho- it has become increasingly clear that secondary lymphoid genic insult can heavily skew the cytokine milieu for T cell organs do not faithfully represent immune responses in the differentiation, jeopardizing immunity to the secondary peripheral tissues. Tissue-specific immunity can be largely pathogenic insult. In response to helminth infection, DCs Downloaded from attributed to resident DC populations that are unique to promote a strong Th2 response that indirectly inhibits Th1 the tissue and have a differential ability to produce innate or CD8 T cell function (128). Helminth infection also cytokines. For example, intestinal DCs at steady-state are drives a regulatory program by promoting the differentiation primarily exposed to commensal microbiota. Therefore, the of alternatively activated macrophages and enhancing 2 gut is enriched with retinoic acid–producing CD11b CD103+ production of TGF-b and IL-10 by DCs (129). A regulatory cells, which specialize in Treg induction (77). During program aids wound healing that helps the worm to navigate http://www.jimmunol.org/ enteric infection, IRF4-dependent CD11b+CD103+ DCs through the host, yet it also drastically inhibits production of populate the gut and drive Th17 cell differentiation by proinflammatory cytokines, like IL-12 and TNF-a,thatare providing TGF-b, IL-6, and IL-23 (112–114). However, crucial for Th1-mediated immunity. This could be a con- when the mucosal barrier is breached, leading to a systemic tributing factor for the widespread prevalence of helminth infection, BATF3-dependent CD8+ DCs, which predominantly coinfection with Mycobacterium and HIV in which Th1 cells reside in the spleen, are activated and produce IL-12 to induce are essential for protection (130, 131). Another prevalent a strong Th1 response (115). Jenkins and colleagues (116) coinfection is the viral bacterial coinfection. How viral infection

elegantly demonstrated the impact of the route of infection on enhances susceptibility to bacterial infection is still an open by guest on September 24, 2021 T cell responses. When injected i.v., L. monocytogenes induced a question, but many potential mechanisms have been Th1 response, whereas intranasal infection with the same strain suggested over the years. Viral infections appear to alter resulted in Th17 differentiation (116). This may be due, in part, metabolic profiles in immune and nonimmune cells that to the IL-6– and TGF-b–producing DC population in the might not be conducive for antibacterial responses (132, nasal-associated lymphoid tissues. Interestingly, the requirement 133). There is also a significant reduction in tolerance for Th17 differentiation also varies based on the priming toward tissue damage during coinfection that can further microenvironment (84). IL-6 was required for Th17 priming in contribute to morbidity and mortality (134). the gut, potentially to overcome the suppressive effects of TGF-b Overall, ongoing and past infections can significantly dictate (84). However, Th17 priming in the spleen, which does not have the quality and strength of innate immune activation. One of TGF-b–producing DCs, was independent of T cell–intrinsic the major challenges in developing successful vaccines is the IL-6R signaling (84). heterogeneity of immune responsiveness toward the vaccine. Similar to the gut, the dermis and epidermis of the skin are Genetic diversity of the population contributes to variability; also populated with specialized DC populations. Langerhans however, it is worthwhile to characterize an individual’s im- cells in the mouse epidermis promote Th17 differentiation mune status as a prognostic tool for predicting the efficacy of following fungal infection in the skin (117). Unlike the epi- immunization. dermis, the dermis is lined by CD103+ DCs that are re- sponsible for cross-presentation to CD8 T cells, as well as Beyond the canonical three signals: microbiota and metabolites generation of Ag-specific Th1 cells (117–120). Therefore, the We have discussed the contextual nature of the three traditional precise location of the pathogen, within a tissue, can also signals that are critical for innate control of adaptive immunity. influence the nature of the resulting T cell response, despite However, it is becoming clear from several recent studies that the fact that the T cells are eventually primed in the lymph the composition of the microbiota and the quality of the node draining the infected area. Moreover, a recently identi- metabolites produced by the commensal microbiota can have fied dermal DC population marked by the expression of considerable influence on myeloid and T cell behavior, es- CD301b was reported to be required for Th2 responses after pecially in the tissues (135). In the absence of infection, innate allergen challenge or worm infections (121). A detailed func- immune cells, such as DCs, provide tolerogenic signals to tional and transcriptional profiling of the CD301b+ population T cells to avoid aberrant T cell activation against innocuous might prove to be useful in predicting the assortment of innate self-antigens. This is primarily achieved by providing self- cytokines that they produce upon activation to identify innate peptide–MHC interactions with self-reactive TCRs in the signals that drive Th2 differentiation. It also remains to be absence of costimulation and inflammatory cytokines. How- 3796 BRIEF REVIEWS: INNATE CUES FOR ADAPTIVE IMMUNITY Downloaded from http://www.jimmunol.org/

FIGURE 1. Linear and complex view of innate control of adaptive immunity. (A) The three-signal paradigm: purified PAMPs activate PRRs on DCs (commonly used ex vivo source of APCs). Mature DCs present the associated Ag onto MHC molecules (signal 1) along with costimulation (signal 2) and innate cytokines (signal 3) to activate and differentiate naive T cells. Activated T cells undergo clonal expansion and produce their respective effector cytokines by guest on September 24, 2021 (measurable parameters), which we referred to as productive immunity, but it may not necessarily provide required protection against a given pathogen. (B) Beyond the three-signal paradigm: successful generation of long-term protective immunity depends on the complex PAMPs and virulence factors associated with the pathogen, with additional inputs generated from the route of infection and immune status of the host. All of these parameters together are sensed by the innate immune cells and converted into meaningful information relayed to T cells. In addition to the three signals mentioned above, T cell responses are intricately modulated by a specific assortment of innate cytokines (IL-1 or type I IFN family), commensal-derived metabolites, and tissue-specific parameters, such as the innate cell type and stromal cell–derived factors. All of these signals together determine how the innate immune system instructs the adaptive immune system to generate protective immunity against specific pathogens. ever, commensal microorganisms pose a unique challenge signaling and are mediated by inhibition of histone deacety- because they possess nonself molecules (PRR ligands), much lases (136). In addition to suppressing proinflammatory re- like virulent pathogens, which can induce all three innate sponses by activated myeloid cells, SCFAs can facilitate M2 signals required for T cell activation and differentiation. polarization of macrophages by directly activating STAT6 Harmful immune activation of the adaptive immune system signaling (138). Whether SCFAs can influence innate control against commensals seems to be contained by the host by of T cell responses has not been directly tested; however, actively sensing microbial-derived metabolites. Commensal butyrate-producing Clostridia was shown to attenuate graft- microbiota produce abundant quantities of short-chain fatty versus-host disease (139), a disease with a strong T cell acids (SCFAs), such as butyrate, acetate, and propionate, as component. Testing the precise role of microbial metabo- end products of the fermentation process. In particular, bu- lites in the innate control of adaptive immunity is challenging, tyrate produced by a certain class of microbiota appears to because butyrate and propionate can also act directly on downregulate LPS-induced proinflammatory cytokine pro- T cells to promote colonic Treg generation and function by duction by lamina propria macrophages (136). Similar find- enhancing FOXP3 transcription (140–142). Moreover, ings were made in human monocyte-derived DCs, in which SCFAs can also affect intestinal homeostasis by acting on butyrate and propionate suppress inflammatory responses by nonimmune cells. The presence of butyrate in colonic crypts reducing the secretion of IL-6, IL-12, and chemokines im- inhibits stem cell proliferation and delays intestinal wound portant for leukocyte trafficking (137). This could have a repair (143). Therefore, deletion of G protein–coupled re- profound effect on suppressing T cell activation induced by ceptors that sense SCFAs specifically in innate immune cells, aberrant recognition of PAMPs on commensal microorgan- such as DCs or macrophages, is required to test the effects of isms that breach the intestinal barrier. Interestingly, the anti- metabolites on the innate control of adaptive immunity. In inflammatory effects of butyrate are independent of TLR addition to SCFA, AHR-binding tryptophan metabolites The Journal of Immunology 3797

(144) and the vitamin A lipid metabolite, retinoic acid, can Similarly, as various DC subsets are being identified, func- control intestinal homeostasis by fine-tuning the Treg/Th17 tional patterns are also becoming apparent. Migratory DCs balance (145). Although the exact role of various metabolites that are critical for Ag delivery to the secondary lymphoid and their mechanism of action are still under investigation, it organs are present in the gut, as well as the skin, and are is clear that metabolites can modulate adaptive immunity characterized by CD103 expression. Likewise, DNGR1+ DCs independently of the innate signals discussed earlier in this were shown to induce tissue-resident memory T cells during review, extending the three-signal paradigm. liver and skin infection (126, 127). These findings point to- Qualitative information about the commensal microbiota ward a possibility of convergent evolution that took place can also be relayed to DCs via epithelial cells. Specific members under diverse tissue-specific immunological pressures and of the microbiota, segmented filamentous bacteria, tightly ad- gave rise to highly specialized, but functionally similar, DC here to the intestinal epithelium and stimulate Th17 differ- subsets. Identifying such underlying principles is going to be entiation (146). Other adhesive bacteria, such as C. rodentium as important as collecting contextual information to reach the and Escherichia coli O157, were also shown to induce Th17 ultimate goal of successfully reverse-engineering the process of responses in an adhesion-dependent manner (147). Adhesion innate control of adaptive immunity and rationally generating of bacteria results in production of serum amyloid A by epi- protective T cell responses. thelial cells that can act on DCs to promote Th17 differentiation (148). It is important to note that the presence of Acknowledgments segmented filamentous bacteria could also promote protective We thank all of the members of the Pasare Lab for helpful discussions and Downloaded from Th17 responses against C. rodentium, suggesting that adhesive critical reading of the manuscript. bacteria are not exposed to APCs but perhaps modulate the DC–T cell interaction milieu (146). How and what about the adhesion of bacteria to the intestinal epithelium is sensed by Disclosures the immune system are not clearly understood and are exciting The authors have no financial conflicts of interest. venues for future research. http://www.jimmunol.org/ References 1. Janeway, C. A., Jr. 1989. Approaching the asymptote? Evolution and revolution in Conclusions immunology. Cold Spring Harb. Symp. Quant. Biol. 54: 1–13. In this review, we attempted to expand our linear under- 2. Curtsinger, J. M., and M. F. Mescher. 2010. 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