During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rαlo exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rαhi memory cells upregulated CD25 and produced IFN-γ, the IL-18Rαlo exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.
Vyšlo v časopise: Exhausted CD8 T Cells Downregulate the IL-18 Receptor and Become Unresponsive to Inflammatory Cytokines and Bacterial Co-infections. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002273 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002273
1. CoxMAZajacAJ 2010 Shaping successful and unsuccessful CD8 T cell responses following infection. J Biomed Biotechnol 2010 159152
2. CuiWKaechSM 2010 Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol Rev 236 151 166
3. SarenevaTMatikainenSKurimotoMJulkunenI 1998 Influenza A virus-induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells. J Immunol 160 6032 6038
4. CousensLPPetersonRHsuSDornerAAltmanJD 1999 Two roads diverged: interferon alpha/beta - and interleukin 12-mediated pathways in promoting T cell interferon gamma responses during viral infection. J Exp Med 189 1315 1328
5. LertmemongkolchaiGCaiGHunterCABancroftGJ 2001 Bystander activation of CD8+ T cells contributes to the rapid production of IFN-gamma in response to bacterial pathogens. J Immunol 166 1097 1105
6. BergRECrossleyEMurraySFormanJ 2003 Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J Exp Med 198 1583 1593
7. KambayashiTAssarssonELukacherAELjunggrenHGJensenPE 2003 Memory CD8+ T cells provide an early source of IFN-gamma. J Immunol 170 2399 2408
8. RaueHPBrienJDHammarlundESlifkaMK 2004 Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18. J Immunol 173 6873 6881
9. BeadlingCSlifkaMK 2005 Differential regulation of virus-specific T-cell effector functions following activation by peptide or innate cytokines. Blood 105 1179 1186
10. BergREFormanJ 2006 The role of CD8 T cells in innate immunity and in antigen non-specific protection. Curr Opin Immunol 18 338 343
11. StrengellMMatikainenSSirenJLehtonenAFosterD 2003 IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 170 5464 5469
12. ShinHWherryEJ 2007 CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol 19 408 415
13. YiJSCoxMAZajacAJ 2010 T-cell exhaustion: characteristics, causes and conversion. Immunology 129 474 481
14. WherryEJHaSJKaechSMHainingWNSarkarS 2007 Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27 670 684
15. MackernessKJCoxMALillyLMWeaverCTHarringtonLE 2010 Pronounced virus-dependent activation drives exhaustion but sustains IFN-gamma transcript levels. J Immunol 185 3643 3651
16. ZajacAJBlattmanJNMurali-KrishnaKSourdiveDJSureshM 1998 Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188 2205 2213
17. FullerMJKhanolkarATeboAEZajacAJ 2004 Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 172 4204 4214
18. ZhouSOuRHuangLPriceGEMoskophidisD 2004 Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection. J Virol 78 3578 3600
19. WherryEJBlattmanJNMurali-KrishnaKvan der MostRAhmedR 2003 Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77 4911 4927
20. FullerMJZajacAJ 2003 Ablation of CD8 and CD4 T cell responses by high viral loads. J Immunol 170 477 486
21. TurtleCJSwansonHMFujiiNEsteyEHRiddellSR 2009 A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity 31 834 844
22. SchinkelAHJonkerJW 2003 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55 3 29
23. HainingWNEbertBLSubrmanianAWherryEJEichbaumQ 2008 Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells. J Immunol 181 1859 1868
24. LuckeyCJBhattacharyaDGoldrathAWWeissmanILBenoistC 2006 Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proc Natl Acad Sci U S A 103 3304 3309
25. HaringJSHartyJT 2009 Interleukin-18-related genes are induced during the contraction phase but do not play major roles in regulating the dynamics or function of the T-cell response to Listeria monocytogenes infection. Infect Immun 77 1894 1903
26. LiWKashiwamuraSUedaHSekiyamaAOkamuraH 2007 Protection of CD8+ T cells from activation-induced cell death by IL-18. J Leukoc Biol 82 142 151
27. IwaiYHemmiHMizeninaOKurodaSSudaK 2008 An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS One 3 e2404
28. WherryEJBarberDLKaechSMBlattmanJNAhmedR 2004 Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci U S A 101 16004 16009
29. ShinHBlackburnSDBlattmanJNWherryEJ 2007 Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J Exp Med 204 941 949
30. FullerMJHildemanDASabbajSGaddisDETeboAE 2005 Cutting edge: emergence of CD127high functionally competent memory T cells is compromised by high viral loads and inadequate T cell help. J Immunol 174 5926 5930
31. LangKSRecherMNavariniAAHarrisNLLohningM 2005 Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. Eur J Immunol 35 738 745
32. GuadalupeMReayESankaranSPrindivilleTFlammJ 2003 Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77 11708 11717
33. BrenchleyJMSchackerTWRuffLEPriceDATaylorJH 2004 CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200 749 759
34. MehandruSPolesMATenner-RaczKHorowitzAHurleyA 2004 Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200 761 770
35. BrenchleyJMPriceDASchackerTWAsherTESilvestriG 2006 Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12 1365 1371
36. JiangWLedermanMMHuntPSiegSFHaleyK 2009 Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199 1177 1185
37. VirginHWWherryEJAhmedR 2009 Redefining chronic viral infection. Cell 138 30 50
38. BlandenRVMimsCA 1973 Macrophage activation in mice infected with ectromelia or lymphocytic choriomeningitis viruses. Aust J Exp Biol Med Sci 51 393 398
39. BartonESWhiteDWCathelynJSBrett-McClellanKAEngleM 2007 Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447 326 329
40. ZunigaEILiouLYMackLMendozaMOldstoneMB 2008 Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections. Cell Host Microbe 4 374 386
41. SunYBrownNKRuddyMJMillerMLLeeY 2009 B and T lymphocyte attenuator tempers early infection immunity. J Immunol 183 1946 1951
42. YiJSIngramJTZajacAJ 2010 IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection. J Immunol 185 4835 4845
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
