Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion

Journal of Immunology

Volumn 193, Issue 4, 2014, Pages 1525-1530

  Ferris, Robert L ^a,b   Lu, Binfeng ^a,b   Kane, Lawrence P ^a,b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; ECALECTIN; HIGH MOBILITY GROUP B1 PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; INTERLEUKIN 1BETA; LYMPHOCYTE ACTIVATION FACTOR 3; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MEMBRANE PROTEIN; MONOCLONAL ANTIBODY; PHOSPHATIDYLINOSITOL 3 KINASE; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN KINASE B; PROTEIN TIM 3; PROTEIN TIM 3 ANTIBODY; PROTEIN TYROSINE KINASE; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR NFAT; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ANTIGEN ANTIBODY COMPLEX; ANTIGEN ANTIBODY REACTION; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; ARTICLE; CANCER IMMUNOTHERAPY; CD3+ T LYMPHOCYTE; CELLULAR DISTRIBUTION; CELLULAR IMMUNITY; CHRONIC DISEASE; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DOWN REGULATION; GENE; GENE DELETION; GENETIC POLYMORPHISM; HEPATITIS C; HOST PATHOGEN INTERACTION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOGENICITY; IMMUNOSTIMULATION; INFECTION RESISTANCE; KNOCKOUT MOUSE; LISTERIOSIS; LUNG NON SMALL CELL CANCER; MEMORY T LYMPHOCYTE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; TIM 3 GENE; TRANSCRIPTION REGULATION; TUBERCULOSIS; TUMOR MICROENVIRONMENT; UPREGULATION;

ANIMALS; ANTIGENS, CD; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL PROLIFERATION; CYTOKINES; HEPACIVIRUS; HIV-1; HUMANS; LYMPHOCYTE ACTIVATION; MEMBRANE PROTEINS; MICE; PROGRAMMED CELL DEATH 1 RECEPTOR; RECEPTORS, ANTIGEN, T-CELL; REPRESSOR PROTEINS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84905967067     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1400557     Document Type: Article

References (62)

1. Virgin, H. W., E. J. Wherry, and R. Ahmed. 2009. Redefining chronic viral infection. Cell 138: 30-50.
2. Wherry, E. J. 2011. T cell exhaustion. Nat. Immunol. 12: 492-499.
3. Odorizzi, P. M., and E. J. Wherry. 2012. Inhibitory receptors on lymphocytes: Insights from infections. J. Immunol. 188: 2957-2965.
4. Sakuishi, K., P. Jayaraman, S. M. Behar, A. C. Anderson, and V. K. Kuchroo. 2011. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 32: 345-349.
5. Drake, C. G., E. Jaffee, and D. M. Pardoll. 2006. Mechanisms of immune evasion by tumors. Adv. Immunol. 90: 51-81.
6. Schietinger, A., and P. D. Greenberg. 2014. Tolerance and exhaustion: Defining mechanisms of T cell dysfunction. Trends Immunol. 35: 51-60.
7. Lipson, E. J., and C. G. Drake. 2011. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clin. Cancer Res. 17: 6958-6962.
8. Gros, A., P. F. Robbins, X. Yao, Y. F. Li, S. Turcotte, E. Tran, J. R. Wunderlich, A. Mixon, S. Farid, M. E. Dudley, et al. 2014. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124: 2246-2259.
9. Yang, Z. Z., D. M. Grote, S. C. Ziesmer, T. Niki, M. Hirashima, A. J. Novak, T. E. Witzig, and S. M. Ansell. 2012. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest. 122: 1271-1282.
10. Topalian, S. L., F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366: 2443-2454.
11. Brahmer, J. R., S. S. Tykodi, L. Q. Chow, W. J. Hwu, S. L. Topalian, P. Hwu, C. G. Drake, L. H. Camacho, J. Kauh, K. Odunsi, et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366: 2455-2465.
12. Hamid, O., C. Robert, A. Daud, F. S. Hodi, W. J. Hwu, R. Kefford, J. D. Wolchok, P. Hersey, R. W. Joseph, J. S. Weber, et al. 2013. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369: 134-144.
13. Sakuishi, K., L. Apetoh, J. M. Sullivan, B. R. Blazar, V. K. Kuchroo, and A. C. Anderson. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207: 2187-2194.
14. Ngiow, S. F., B. von Scheidt, H. Akiba, H. Yagita, M. W. Teng, and M. J. Smyth. 2011. Anti-TIM3 antibody promotes T cell IFN-g-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71: 3540-3551.
15. Fourcade, J., Z. Sun, M. Benallaoua, P. Guillaume, I. F. Luescher, C. Sander, J. M. Kirkwood, V. Kuchroo, and H. M. Zarour. 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207: 2175-2186.
16. Sakuishi, K., S. F. Ngiow, J. M. Sullivan, M. W. Teng, V. K. Kuchroo, M. J. Smyth, and A. C. Anderson. 2013. TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. OncoImmunology 2: E23849.
17. Gao, X., Y. Zhu, G. Li, H. Huang, G. Zhang, F. Wang, J. Sun, Q. Yang, X. Zhang, and B. Lu. 2012. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS ONE 7: E30676.
18. Allen, S. J., P. Hamrah, D. Gate, K. R. Mott, D. Mantopoulos, L. Zheng, T. Town, C. Jones, U. H. von Andrian, G. J. Freeman, et al. 2011. The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1. J. Virol. 85: 4184-4197.
19. Angelosanto, J. M., and E. J. Wherry. 2010. Transcription factor regulation of CD8 + T-cell memory and exhaustion. Immunol. Rev. 236: 167-175.
20. Barber, D. L., E. J. Wherry, D. Masopust, B. Zhu, J. P. Allison, A. H. Sharpe, G. J. Freeman, and R. Ahmed. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682-687.
21. Blackburn, S. D., H. Shin, W. N. Haining, T. Zou, C. J. Workman, A. Polley, M. R. Betts, G. J. Freeman, D. A. Vignali, and E. J. Wherry. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10: 29-37.
22. Day, C. L., D. E. Kaufmann, P. Kiepiela, J. A. Brown, E. S. Moodley, S. Reddy, E. W. Mackey, J. D. Miller, A. J. Leslie, C. DePierres, et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 350-354.
23. Jin, H. T., A. C. Anderson, W. G. Tan, E. E. West, S. J. Ha, K. Araki, G. J. Freeman, V. K. Kuchroo, and R. Ahmed. 2010. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 107: 14733-14738.
24. Nakamoto, N., H. Cho, A. Shaked, K. Olthoff, M. E. Valiga, M. Kaminski, E. Gostick, D. A. Price, G. J. Freeman, E. J. Wherry, and K. M. Chang. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5: E1000313.
25. Shin, H., and E. J. Wherry. 2007. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19: 408-415.
26. Jones, R. B., L. C. Ndhlovu, J. D. Barbour, P. M. Sheth, A. R. Jha, B. R. Long, J. C. Wong, M. Satkunarajah, M. Schweneker, J. M. Chapman, et al. 2008. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205: 2763-2779.
27. Kassu, A., R. A. Marcus, M. B. D'Souza, E. A. Kelly-McKnight, L. Golden-Mason, R. Akkina, A. P. Fontenot, C. C. Wilson, and B. E. Palmer. 2010. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185: 3007-3018.
28. Kassu, A., R. A. Marcus, M. B. D'Souza, E. A. Kelly-McKnight, and B. E. Palmer. 2011. Suppression of HIV replication by antiretroviral therapy reduces TIM-3 expression on HIV-specific CD8(+) T cells. AIDS Res. Hum. Retroviruses 27: 1-3.
29. Golden-Mason, L., B. E. Palmer, N. Kassam, L. Townshend-Bulson, S. Livingston, B. J. McMahon, N. Castelblanco, V. Kuchroo, D. R. Gretch, and H. R. Rosen. 2009. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83: 9122-9130.
30. McMahan, R. H., L. Golden-Mason, M. I. Nishimura, B. J. McMahon, M. Kemper, T. M. Allen, D. R. Gretch, and H. R. Rosen. 2010. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J. Clin. Invest. 120: 4546-4557.
31. Jayaraman, P., I. Sada-Ovalle, S. Beladi, A. C. Anderson, V. Dardalhon, C. Hotta, V. K. Kuchroo, and S. M. Behar. 2010. Tim3 binding to galectin-9 stimulates antimicrobial immunity. J. Exp. Med. 207: 2343-2354.
32. Sada-Ovalle, I., L. Chávez-Galán, L. Torre-Bouscoulet, L. Nava-Gamin?o, L. Barrera, P. Jayaraman, M. Torres-Rojas, M. A. Salazar-Lezama, and S. M. Behar. 2012. The Tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with Mycobacterium tuberculosis. J. Immunol. 189: 5896-5902.
33. Qiu, Y., J. Chen, H. Liao, Y. Zhang, H. Wang, S. Li, Y. Luo, D. Fang, G. Li, B. Zhou, et al. 2012. Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. PLoS Pathog. 8: E1002984.
34. Gorman, J. V., G. Starbeck-Miller, N. L. Pham, G. L. Traver, P. B. Rothman, J. T. Harty, and J. D. Colgan. 2014. Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J. Immunol. 192: 3133-3142.
35. Lee, J., E. W. Su, C. Zhu, S. Hainline, J. Phuah, J. A. Moroco, T. E. Smithgall, V. K. Kuchroo, and L. P. Kane. 2011. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol. Cell. Biol. 31: 3963-3974.
36. Han, G., G. Chen, B. Shen, and Y. Li. 2013. Tim-3: An Activation Marker and Activation Limiter of Innate Immune Cells. Front. Immunol. 4: 449.
37. Anderson, A. C., D. E. Anderson, L. Bregoli, W. D. Hastings, N. Kassam, C. Lei, R. Chandwaskar, J. Karman, E. W. Su, M. Hirashima, et al. 2007. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318: 1141-1143.
38. Nakae, S., M. Iikura, H. Suto, H. Akiba, D. T. Umetsu, R. H. Dekruyff, H. Saito, and S. J. Galli. 2007. TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells. Blood 110: 2565-2568.
39. Chiba, S., M. Baghdadi, H. Akiba, H. Yoshiyama, I. Kinoshita, H. Dosaka-Akita, Y. Fujioka, Y. Ohba, J. V. Gorman, J. D. Colgan, et al. 2012. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13: 832-842.
40. Zhang, Y., C. J. Ma, J. M. Wang, X. J. Ji, X. Y. Wu, Z. S. Jia, J. P. Moorman, and Z. Q. Yao. 2011. Tim-3 negatively regulates IL-12 expression by monocytes in HCV infection. PLoS ONE 6: E19664.
41. Zhang, Y., C. J. Ma, J. M. Wang, X. J. Ji, X. Y.Wu, J. P. Moorman, and Z. Q. Yao. 2012. Tim-3 regulates pro-and anti-inflammatory cytokine expression in human CD14+ monocytes. J. Leukoc. Biol. 91: 189-196.
42. Yang, X., X. Jiang, G. Chen, Y. Xiao, S. Geng, C. Kang, T. Zhou, Y. Li, X. Guo, H. Xiao, et al. 2013. T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response. J. Immunol. 190: 2068-2079.
43. Van De Weyer, P. S., M. Muehlfeit, C. Klose, J. V. Bonventre, G. Walz, and E. W. Kuehn. 2006. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem. Biophys. Res. Commun. 351: 571-576.
44. C.layton, K. L., M. S. Haaland, M. B. Douglas-Vail, S. Mujib, G. M. Chew, L. C. Ndhlovu, and M. A. Ostrowski. 2014. T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J. Immunol. 192: 782-791.
45. Abraham, R. T., and A. Weiss. 2004. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat. Rev. Immunol. 4: 301-308.
46. Rangachari, M., C. Zhu, K. Sakuishi, S. Xiao, J. Karman, A. Chen, M. Angin, A. Wakeham, E. A. Greenfield, R. A. Sobel, et al. 2012. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat. Med. 18: 1394-1400.
47. Chemnitz, J. M., R. V. Parry, K. E. Nichols, C. H. June, and J. L. Riley. 2004. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173: 945-954.
48. Richter, K., T. Brocker, and A. Oxenius. 2012. Antigen amount dictates CD8+ Tcell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell. Eur. J. Immunol. 42: 2290-2304.
49. Mueller, S. N., and R. Ahmed. 2009. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 106: 8623-8628.
50. Hand, T. W., W. Cui, Y. W. Jung, E. Sefik, N. S. Joshi, A. Chandele, Y. Liu, and S. M. Kaech. 2010. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc. Natl. Acad. Sci. USA 107: 16601-16606.
51. Macintyre, A. N., D. Finlay, G. Preston, L. V. Sinclair, C. M. Waugh, P. Tamas, C. Feijoo, K. Okkenhaug, and D. A. Cantrell. 2011. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34: 224-236.
52. Kim, E. H., J. A. Sullivan, E. H. Plisch, M. M. Tejera, A. Jatzek, K. Y. Choi, and M. Suresh. 2012. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J. Immunol. 188: 4305-4314.
53. Laplante, M., and D. M. Sabatini. 2012. mTOR signaling in growth control and disease. Cell 149: 274-293.
54. Araki, K., A. P. Turner, V. O. Shaffer, S. Gangappa, S. A. Keller, M. F. Bachmann, C. P. Larsen, and R. Ahmed. 2009. mTOR regulates memory CD8 T-cell differentiation. Nature 460: 108-112.
55. Rao, R. R., Q. Li, K. Odunsi, and P. A. Shrikant. 2010. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32: 67-78.
56. Lucas, C. L., H. S. Kuehn, F. Zhao, J. E. Niemela, E. K. Deenick, U. Palendira, D. T. Avery, L. Moens, J. L. Cannons, M. Biancalana, et al. 2014. Dominantactivating germline mutations in the gene encoding the PI(3)K catalytic subunit p110d result in T cell senescence and human immunodeficiency. Nat. Immunol. 15: 88-97.
57. Simpson, T. R., F. Li,W. Montalvo-Ortiz, M. A. Sepulveda, K. Bergerhoff, F. Arce, C. Roddie, J. Y. Henry, H. Yagita, J. D. Wolchok, et al. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210: 1695-1710.
58. Bulliard, Y., R. Jolicoeur, M. Windman, S. M. Rue, S. Ettenberg, D. A. Knee, N. S. Wilson, G. Dranoff, and J. L. Brogdon. 2013. Activating Fc g receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210: 1685-1693.
59. Eastwood, D., L. Findlay, S. Poole, C. Bird, M. Wadhwa, M. Moore, C. Burns, R. Thorpe, and R. Stebbings. 2010. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory Tcells. Br. J. Pharmacol. 161: 512-526.
60. Horvath, C., L. Andrews, A. Baumann, L. Black, D. Blanset, J. Cavagnaro, K. L. Hastings, D. L. Hutto, T. K. MacLachlan, M. Milton, et al. 2012. Storm forecasting: Additional lessons from the CD28 superagonist TGN1412 trial. Nat. Rev. Immunol. 12: 740-, author reply 740.
61. Hünig, T. 2012. The storm has cleared: Lessons from the CD28 superagonist TGN1412 trial. Nat. Rev. Immunol. 12: 317-318.
62. Suntharalingam, G., M. R. Perry, S. Ward, S. J. Brett, A. Castello-Cortes, M. D. Brunner, and N. Panoskaltsis. 2006. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355: 1018-1028.