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

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Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm 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 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology 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 re- quirements 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
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