Enhanced CD8 T Cell Responses through GITR-Mediated Costimulation Resolve Chronic Viral Infection

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The ability of the immune system to rapidly respond to a viral infection is a prerequisite for the survival of an individual. The immediate reaction of innate immune cells and the subsequent response of antigen-specific lymphocytes is usually effective for rapid neutralization and removal of the invading virus. Yet, such protective immune responses need to be well controlled, as they can cause severe tissue damage that may disable the host more than the infection itself. One way that has evolutionarily been proven effective to deal with this balancing act between protective immunity and prevention of immunopathology is to render virus-specific T cells “exhausted” when the virus cannot be eradicated and the host becomes chronically infected. Exhausted T cells progressively lose their ability to kill other cells and produce different cytokines. The benefit of this exhausted state of anti-viral immunity is that it induces less tissue damage, but the downside is obviously less efficient control over the viral infection. Many immunotherapeutic and vaccination strategies against chronic viral infections are currently dedicated to overcome the exhausted state of the virus-specific T cells and thereby clear the virus. However, the accompanying risk is an exaggerated immune response with overt immunopathology. Here we describe in a mouse model that enhanced triggering through the costimulatory molecule GITR on T cells is able to provide protection upon viral infection and clear an otherwise persistent virus, but importantly without the development of collateral damage due to immunopathology. We show that GITR-mediated costimulation enhances a protective CD8 T cell response, for which CD4 T cell help is required. Our study provides new insights in how a particular costimulatory pathway can be utilized to boost anti-viral immunity, which is highly relevant for the development of safe immunotherapeutic strategies against chronic viral infections in humans.

Vyšlo v časopise: Enhanced CD8 T Cell Responses through GITR-Mediated Costimulation Resolve Chronic Viral Infection. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004675
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004675

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Zdroje

1. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12: 492–499. 21739672

2. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355: 1018–1028. 16908486

3. Amos SM, Duong CP, Westwood JA, Ritchie DS, Junghans RP, Darcy PK, et al. (2011) Autoimmunity associated with immunotherapy of cancer. Blood 118: 499–509. doi: 10.1182/blood-2011-01-325266 21531979

4. Zinkernagel RM, Oldstone MB (1976) Cells that express viral antigens but lack H-2 determinants are not lysed by immune thymus-derived lymphocytes but are lysed by other antiviral immune attack mechanisms. Proc Natl Acad Sci U S A 73: 3666–3670. 1086476

5. Wilson EB, Brooks DG (2010) Translating insights from persistent LCMV infection into anti-HIV immunity. Immunol Res 48: 3–13. doi: 10.1007/s12026-010-8162-1 20725865

6. Gallimore A, Glithero A, Godkin A, Tissot AC, Pluckthun A, Elliott T, et al. (1998) Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med 187: 1383–1393. 9565631

7. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188: 2205–2213. 9858507

8. Battegay M, Moskophidis D, Rahemtulla A, Hengartner H, Mak TW, Zinkernagel RM (1994) Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J Virol 68: 4700–4704. 7911534

9. Matloubian M, Concepcion RJ, Ahmed R (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68: 8056–8063. 7966595

10. Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, Gangappa S, et al. (2007) Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci U S A 104: 15430–15435. 17878315

11. Mueller SN, Vanguri VK, Ha SJ, West EE, Keir ME, Glickman JN, et al. (2010) PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J Clin Invest 120: 2508–2515. doi: 10.1172/JCI40040 20551512

12. Binder D, van den Broek MF, Kagi D, Bluethmann H, Fehr J, Hengartner H, et al. (1998) Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus. J Exp Med 187: 1903–1920. 9607930

13. Odermatt B, Eppler M, Leist TP, Hengartner H, Zinkernagel RM (1991) Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure. Proc Natl Acad Sci U S A 88: 8252–8256. 1910175

14. Matter M, Odermatt B, Yagita H, Nuoffer JM, Ochsenbein AF (2006) Elimination of chronic viral infection by blocking CD27 signaling. J Exp Med 203: 2145–2155. 16923852

15. Nolte MA, van Olffen RW, van Gisbergen KP, Van Lier RA (2009) Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev 229: 216–231. doi: 10.1111/j.1600-065X.2009.00774.x 19426224

16. Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9: 271–285. doi: 10.1038/nri2526 19319144

17. Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23: 23–68. 15771565

18. Nocentini G, Ronchetti S, Petrillo MG, Riccardi C (2012) Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. Br J Pharmacol 165: 2089–2099. doi: 10.1111/j.1476-5381.2011.01753.x 22029729

19. Clouthier DL, Watts TH (2014) Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection. Cytokine Growth Factor Rev doi: 10.1016/j.cytogfr.2013.12.003

20. Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, et al. (2003) Cloning and characterization of GITR ligand. Genes Immun 4: 564–569. 14647196

21. Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, et al. (2003) Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A 100: 15059–15064. 14608036

22. Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, et al. (2004) Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173: 5008–5020. 15470044

23. Suvas S, Kim B, Sarangi PP, Tone M, Waldmann H, Rouse BT (2005) In vivo kinetics of GITR and GITR ligand expression and their functional significance in regulating viral immunopathology. J Virol 79: 11935–11942. 16140769

24. Ji HB, Liao G, Faubion WA, Abadia-Molina AC, Cozzo C, Laroux FS, et al. (2004) Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol 172: 5823–5827. 15128759

25. Ronchetti S, Zollo O, Bruscoli S, Agostini M, Bianchini R, Nocentini G, et al. (2004) GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 34: 613–622. 14991590

26. Ronchetti S, Nocentini G, Bianchini R, Krausz LT, Migliorati G, Riccardi C (2007) Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells. J Immunol 179: 5916–5926. 17947665

27. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3: 135–142. 11812990

28. Cohen AD, Diab A, Perales MA, Wolchok JD, Rizzuto G, Merghoub T, et al. (2006) Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res 66: 4904–4912. 16651447

29. Cote AL, Zhang P, O’Sullivan JA, Jacobs VL, Clemis CR, Sakaguchi S, et al. (2011) Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens. J Immunol 186: 275–283. doi: 10.4049/jimmunol.1001308 21106849

30. Ramirez-Montagut T, Chow A, Hirschhorn-Cymerman D, Terwey TH, Kochman AA, Lu S, et al. (2006) Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J Immunol 176: 6434–6442. 16709800

31. Nocentini G, Riccardi C (2009) GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 647: 156–173. doi: 10.1007/978-0-387-89520-8_11 19760073

32. Ephrem A, Epstein AL, Stephens GL, Thornton AM, Glass D, Shevach EM (2013) Modulation of Treg cells/T effector function by GITR signaling is context-dependent. Eur J Immunol 43: 2421–2429. doi: 10.1002/eji.201343451 23722868

33. van Olffen RW, Koning N, van Gisbergen KP, Wensveen FM, Hoek RM, Boon L, et al. (2009) GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo. J Immunol 182: 7490–7500. doi: 10.4049/jimmunol.0802751 19494272

34. Carrier Y, Whitters MJ, Miyashiro JS, LaBranche TP, Ramon HE, Benoit SE, et al. (2012) Enhanced GITR/GITRL interactions augment IL-27 expression and induce IL-10-producing Tr-1 like cells. Eur J Immunol 42: 1393–1404. doi: 10.1002/eji.201142162 22678896

35. Crotty S, McCausland MM, Aubert RD, Wherry EJ, Ahmed R (2006) Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease. Blood 108: 3085–3093. 16788096

36. Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG (2011) Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J Exp Med 208: 987–999. doi: 10.1084/jem.20101773 21536743

37. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, et al. (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325: 1006–1010. doi: 10.1126/science.1175870 19608860

38. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. (2014) Molecular and Transcriptional Basis of CD4(+) T Cell Dysfunction during Chronic Infection. Immunity 40: 289–302. doi: 10.1016/j.immuni.2014.01.005 24530057

39. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, et al. (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16: 311–323. 11869690

40. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, et al. (2007) Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27: 281–295. 17723218

41. Olson JA, McDonald-Hyman C, Jameson SC, Hamilton SE (2013) Effector-like CD8(+) T cells in the memory population mediate potent protective immunity. Immunity 38: 1250–1260. doi: 10.1016/j.immuni.2013.05.009 23746652

42. Mueller SN, Ahmed R (2009) High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 106: 8623–8628. doi: 10.1073/pnas.0809818106 19433785

43. Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP (2003) CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421: 852–856. 12594515

44. Schulze Zur Wiesch J, Ciuffreda D, Lewis-Ximenez L, Kasprowicz V, Nolan BE, Streeck H, et al. (2012) Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med 209: 61–75. doi: 10.1084/jem.20100388 22213804

45. Hangartner L, Zinkernagel RM, Hengartner H (2006) Antiviral antibody responses: the two extremes of a wide spectrum. Nat Rev Immunol 6: 231–243. 16498452

46. Angelosanto JM, Blackburn SD, Crawford A, Wherry EJ (2012) Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J Virol 86: 8161–8170. doi: 10.1128/JVI.00889-12 22623779

47. Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ (2010) Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol 84: 2078–2089. doi: 10.1128/JVI.01579-09 19955307

48. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, et al. (2011) Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 12: 663–671. doi: 10.1038/ni.2046 21623380

49. Kim J, Choi WS, Kang H, Kim HJ, Suh JH, Sakaguchi S, et al. (2006) Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid-induced TNF receptor. J Immunol 176: 5223–5231. 16621987

50. Snell LM, McPherson AJ, Lin GH, Sakaguchi S, Pandolfi PP, Riccardi C, et al. (2010) CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection. J Immunol 185: 7223–7234. doi: 10.4049/jimmunol.1001912 21076066

51. Clouthier DL, Zhou AC, Watts TH (2014) Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC. J Immunol 193: 5033–5043. doi: 10.4049/jimmunol.1401002 25281716

52. Ronchetti S, Nocentini G, Petrillo MG, Riccardi C (2012) CD8+ T cells: GITR matters. ScientificWorldJournal 2012: 308265. doi: 10.1100/2012/308265 22654588

53. Cook KD, Whitmire JK (2013) The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J Immunol 190: 641–649. doi: 10.4049/jimmunol.1202448 23241878

54. Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, et al. (2012) Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A 109: 1210–1215. doi: 10.1073/pnas.1118834109 22167808

55. Srivastava S, Koch MA, Pepper M, Campbell DJ (2014) Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 211: 961–974. doi: 10.1084/jem.20131556 24711580

56. Punkosdy GA, Blain M, Glass DD, Lozano MM, O’Mara L, Dudley JP, et al. (2011) Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc Natl Acad Sci U S A 108: 3677–3682. doi: 10.1073/pnas.1100213108 21321220

57. Nolte MA, Van Lier RA (2006) The price of the CD27-CD70 costimulatory axis: you can’t have it all. J Exp Med 203: 2405–2408. 17060478

58. Boettler T, Moeckel F, Cheng Y, Heeg M, Salek-Ardakani S, Crotty S, et al. (2012) OX40 facilitates control of a persistent virus infection. PLoS Pathog 8: e1002913. doi: 10.1371/journal.ppat.1002913 22969431

59. Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X (2014) Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J Transl Med 12: 36. doi: 10.1186/1479-5876-12-36 24502656

60. He H, Messer RJ, Sakaguchi S, Yang G, Robertson SJ, Hasenkrug KJ (2004) Reduction of retrovirus-induced immunosuppression by in vivo modulation of T cells during acute infection. J Virol 78: 11641–11647. 15479805

61. Dittmer U, He H, Messer RJ, Schimmer S, Olbrich AR, Ohlen C, et al. (2004) Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity 20: 293–303. 15030773

62. Ahmed R, Salmi A, Butler LD, Chiller JM, Oldstone MB (1984) Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med 160: 521–540. 6332167

63. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al. (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274: 94–96. 8810254