Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion Robert L. Ferris, Binfeng Lu and Lawrence P. Kane This information is current as J Immunol 2014; 193:1525-1530; ; of September 26, 2021. doi: 10.4049/jimmunol.1400557 http://www.jimmunol.org/content/193/4/1525 Downloaded from References This article cites 61 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/193/4/1525.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 26, 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion Robert L. Ferris,*,†,‡ Binfeng Lu,*,‡ and Lawrence P. Kane*,‡ T cell exhaustion is thought to be a natural mechanism and effector molecules, with IL-2, cytotoxicity and proliferation for limiting immune pathology, although it may be de- among the earliest affected functions and IFN-g among the sirable to circumvent this mechanism to help eliminate latest (1, 2). Exhausted T cells also may become “addicted” to viral reservoirs or tumors. Although there are no defin- AgR signals and lose responsiveness to the homeostatic cyto- itive markers, a fingerprint for exhausted T cells has kine IL-7, with the latter due in part to loss of CD127 (IL-7r been described that includes the transmembrane pro- a-chain) expression (2). Importantly, for possible therapeutic teins PD-1, LAG3, and Tim-3. However, apart from reversal, exhausted T cells also gain high-level and persistent, as the recruitment of tyrosine phosphatases to PD-1, little opposed to transient, expression of several proteins, including Downloaded from is known about the biochemical mechanisms by which the transcription factor BLIMP-1 and the transmembrane these proteins contribute to the development or main- proteins PD-1, Tim-3, and LAG3 (1, 2). The latter proteins, tenance of exhaustion. Tim-3 contains no known motifs so-called “checkpoint” receptors, have attracted attention as possible dominant mediators of T cell exhaustion because Abs for the recruitment of inhibitory phosphatases, but it to these proteins or their ligands can sometimes rescue the may actually increase signaling downstream of TCR/ function of exhausted T cells (2–4). Because this topic has been http://www.jimmunol.org/ CD3, at least under acute conditions. Other studies covered extensively in other relatively recent reviews (1, 2), we showed that T cell exhaustion results from chronic stim- focus mainly on recent studies of Tim-3, which has attracted ulation that extends the effector phase of T cell activa- substantial preclinical attention of late as a novel therapeutic tion, at the expense of T cell memory. We suggest that target for reversal of T cell exhaustion. We also review what is Tim-3 may contribute to T cell exhaustion by enhancing known regarding signal transduction pathways implicated in TCR-signaling pathways. The Journal of Immunology, Tim-3 function. Finally, we discuss the role of TCR signaling 2014, 193: 1525–1530. in driving the development of exhaustion and how this might be influenced by Tim-3. by guest on September 26, 2021 cell activation, including development of a robust Lessons from tumors memory response, is critical for the development of an The tumor microenvironment is known to be immunosup- efficient immune response to viral infection and can also T pressive as a result of inhibitory signals from cell surface and be instrumental in mounting an immune response to solid soluble mediators (5), although the precise strategies used by tumors. However, overly vigorous or sustained immune responses different tumors can vary by tissue and even from patient to can cause immune-mediated pathology that is detrimental to the patient. Although T cells specific to tumor Ags can be readily host. Such a problem is particularlyevidentwithvirusesthatcause isolated from solid tumors of patients and in mouse models, chronic infections (1). In these cases, the sustained presence of these cells often respond poorly to ex vivo stimulation. This T viral Ags appears to drive the formation of a state of Ag-specific cell dysfunction is thought to result, at least in part, from T cell exhaustion. Although this has the beneficial effect of exhaustion (or over-stimulation) of effector tumor-infiltrating limiting immune pathology, it can result in the establishment lymphocytes. T cell exhaustion is caused by chronic antigenic of a viral reservoir that may become reactivated under conditions stimulation and expression of inhibitory coreceptors and of physiological stress. T cell exhaustion can also be detrimental cytokines, among other factors (6). Based on the recent suc- when it impairs the ability of an adaptive immune response to cess of CTLA-4 Ab therapy (7), as well as accumulating data eliminate a tumor. from preclinical models, there is now considerable excitement Functionally, the development of T cell exhaustion is char- surrounding molecules whose targeting may allow for broad acterized by the gradual loss of expression of various cytokines enhancement of T cell responses against tumors. Solid tu- *Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Address correspondence and reprint requests to Dr. Lawrence P. Kane, Department of PA 15261; †Department of Otolaryngology, University of Pittsburgh School of Medi- Immunology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261. cine, Pittsburgh, PA 15261; and ‡Cancer Immunology Program, University of Pitts- E-mail address: [email protected] burgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA Abbreviations used in this article: gal9, galectin-9; HCV, hepatitis C virus; mTORC1, 15261 mTOR complex 1; SH2, Src homology 2; TB, tuberculosis; Treg, regulatory T cell; WT, ORCID: 0000-0001-5198-516X (L.P.K.). wild-type. Received for publication February 28, 2014. Accepted for publication May 13, 2014. Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 This work was supported by National Institutes of Health Grants DE019727 and CA097190 (to R.L.F.), CA167229 and CA097190 (to B.L.), and AI109605 and AI073748 (to L.P.K.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400557 1526 BRIEF REVIEWS: SIGNALING AND T CELL EXHAUSTION mor–infiltrating T cells often express high levels of one or ligands—galectin-9 (gal9), expressed on macrophages— more inhibitory or exhaustion-associated receptors, including stimulated the production of the cytokine IL-1b, enhancing PD-1, LAG3, and/or Tim-3. Indeed, consistent with Ag bacterial killing. This effect was mimicked by administration acting as a driver of exhaustion, a recent study on melanoma of Tim-3–Ig fusion protein, through its interaction with gal9. patients demonstrated that PD-1 can be used to prospectively A similar phenomenon was observed in human macrophages distinguish tumor-specific T cells at the tumor site (8). Tim-3 (32). At this point, the nature of the signal transmitted by expression on T cells is also seen in the context of nonsolid gal9 after Tim-3 binding is unknown. Still, this finding is of tumors. For example, upregulation of Tim-3 (possibly driven by possible relevance for the interpretation of multiple other IL-12) on effector T cells of patients with follicular B cell non- studies, because a soluble Tim-3–Ig fusion protein is often Hodgkin lymphoma was associated with poor outcomes (9). used as a blocking reagent in other settings. Returning to PD-1 has been extensively studied as a potential therapeutic T cells and human patients, active TB, as opposed to latent target, and recent clinical trial data suggest that mAbs to PD-1 infection, is associated with the upregulation of Tim-3 on or one of its ligands, PD-L1, are clinically effective against both CD4+ and CD8+ T cells (33). Surprisingly, however, certain solid tumors, including melanoma, as well as non-small these Tim-3+ T cells display more potent anti-TB responses, cell lung cancer, generally regarded as a nonimmunogenic contrary to what has been observed in chronic viral infection. tumor (10–12). mAbs specific for Tim-3 also were shown to Although the reasons for these differences are not clear, the promote rejection of solid tumors in murine models (13, 14), investigators speculated that they may be due to the somewhat + and mAbs to human Tim-3 can rescue the ex vivo function divergent phenotypes of Tim-3 TB-specific T cells compared Downloaded from of apparently exhausted T cells from tumor-bearing patients with Tim-3+ T cells found in HIV and HCV patients. For (15). In the former case, the efficacy of Tim-3 mAb therapy example, Tim-3+ T cells in TB patients were found to express appeared to result, at least in part, from effects on regulatory CD127 (IL-7r a-chain) (33), whereas this marker is well T cells (Tregs), which also can express Tim-3 (16). Strikingly, known to be lost in exhausted T cells (including those that are these Tim-3+ Tregs appear to be among the most potent at Tim-3+) during chronic viral infections of humans and mice inhibiting effector T cell function and express greater levels of (1, 2).