Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection


While T cells are required for protection against Mycobacterium tuberculosis infection, attempts to prevent tuberculosis by vaccines designed to elicit memory T cells have only been partially successful. Several vaccine candidates are in clinical trials, but progress has been slow because their ability to prevent disease must be empirically tested. There is little understanding of why certain antigens are targets of protective immunity. We have characterized an immunodominant CD8+ T cell response to the M. tuberculosis antigen TB10.4 (EsxH). CD8+ T cells specific for the TB10.44–11 epitope are primed early during infection and account for 30–50% of lung CD8+ T cells during chronic infection. Now we have used deep sequencing to characterize the TCR repertoire of TB10.44-11-specific CD8+ T cells in the lungs of infected mice. Interestingly, TB10.44-11-specific CD8+ T cells exhibit extreme clonal expansion of certain TCRβ with common structural features, most likely because of affinity selection. Affinity selection of T cells is more important when antigen presentation is limiting. Although the lung contains numerous bacteria during infection, antigen-presentation by infected APC may be limiting, mimicking a “low antigen” state. Thus, even T cells that have the potential to mediate protection may function inefficiently because of suboptimal T cell activation.


Vyšlo v časopise: Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004849
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004849

Souhrn

While T cells are required for protection against Mycobacterium tuberculosis infection, attempts to prevent tuberculosis by vaccines designed to elicit memory T cells have only been partially successful. Several vaccine candidates are in clinical trials, but progress has been slow because their ability to prevent disease must be empirically tested. There is little understanding of why certain antigens are targets of protective immunity. We have characterized an immunodominant CD8+ T cell response to the M. tuberculosis antigen TB10.4 (EsxH). CD8+ T cells specific for the TB10.44–11 epitope are primed early during infection and account for 30–50% of lung CD8+ T cells during chronic infection. Now we have used deep sequencing to characterize the TCR repertoire of TB10.44-11-specific CD8+ T cells in the lungs of infected mice. Interestingly, TB10.44-11-specific CD8+ T cells exhibit extreme clonal expansion of certain TCRβ with common structural features, most likely because of affinity selection. Affinity selection of T cells is more important when antigen presentation is limiting. Although the lung contains numerous bacteria during infection, antigen-presentation by infected APC may be limiting, mimicking a “low antigen” state. Thus, even T cells that have the potential to mediate protection may function inefficiently because of suboptimal T cell activation.


Zdroje

1. Davis MM, Bjorkman PJ (1988) T-cell antigen receptor genes and T-cell recognition [published erratum appears in Nature 1988 Oct 20;335(6192):744]. Nature 334: 395–402. 3043226

2. Venturi V, Price DA, Douek DC, Davenport MP (2008) The molecular basis for public T-cell responses? Nature Reviews Immunology 8: 231–238. doi: 10.1038/nri2260 18301425

3. Jenkins MK, Chu HH, McLachlan JB, Moon JJ (2010) On the composition of the preimmune repertoire of T cells specific for Peptide-major histocompatibility complex ligands. Annual Review of Immunology 28: 275–294. doi: 10.1146/annurev-immunol-030409-101253 20307209

4. Plumlee CR, Sheridan BS, Cicek BB, Lefrancois L (2013) Environmental cues dictate the fate of individual CD8+ T cells responding to infection. Immunity 39: 347–356. doi: 10.1016/j.immuni.2013.07.014 23932571

5. Obar JJ, Khanna KM, Lefrancois L (2008) Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28: 859–869. doi: 10.1016/j.immuni.2008.04.010 18499487

6. Kotturi MF, Scott I, Wolfe T, Peters B, Sidney J, et al. (2008) Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J Immunol 181: 2124–2133. 18641351

7. Jenkins MK, Moon JJ (2012) The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J Immunol 188: 4135–4140. doi: 10.4049/jimmunol.1102661 22517866

8. Blythe MJ, Zhang Q, Vaughan K, de CR Jr., Salimi N, et al. (2007) An analysis of the epitope knowledge related to Mycobacteria. ImmunomeRes 3: 10. 18081934

9. Majlessi L, Rojas MJ, Brodin P, Leclerc C (2003) CD8+-T-cell responses of Mycobacterium-infected mice to a newly identified major histocompatibility complex class I-restricted epitope shared by proteins of the ESAT-6 family. Infection and Immunity 71: 7173–7177. 14638811

10. Woodworth JS, Shin D, Volman M, Nunes-Alves C, Fortune SM, et al. (2011) Mycobacterium tuberculosis directs immunofocusing of CD8+ T cell responses despite vaccination. J Immunol 186: 1627–1637. doi: 10.4049/jimmunol.1002911 21178003

11. Hoang TTKT, Nansen A, Roy S, Billeskov R, Aagaard C, et al. (2009) Distinct differences in the expansion and phenotype of TB10.4 specific CD8 and CD4 T cells after infection with Mycobacterium tuberculosis. PLoS ONE 4: e5928. doi: 10.1371/journal.pone.0005928 19529765

12. Axelsson-Robertson R, Weichold F, Sizemore D, Wulf M, Skeiky YAW, et al. (2010) Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)-B*0702 and HLA-B*0801 alleles in TB10.4 CD8 T-cell responses. Immunology 129: 496–505. doi: 10.1111/j.1365-2567.2009.03201.x 20002212

13. Axelsson-Robertson R, Loxton AG, Walzl G, Ehlers MM, Kock MM, et al. (2013) A broad profile of co-dominant epitopes shapes the peripheral Mycobacterium tuberculosis specific CD8+ T-cell immune response in South African patients with active tuberculosis. PLoS One 8: e58309. doi: 10.1371/journal.pone.0058309 23555576

14. Divangahi M, Desjardins D, Nunes-Alves C, Remold HG, Behar SM (2010) Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis. Nat Immunol 11: 751–758. doi: 10.1038/ni.1904 20622882

15. Nobrega C, Nunes-Alves C, Cerqueira-Rodrigues B, Roque S, Barreira-Silva P, et al. (2013) T cells home to the thymus and control infection. J Immunol 190: 1646–1658. doi: 10.4049/jimmunol.1202412 23315077

16. Billeskov R, Vingsbo-Lundberg C, Andersen P, Dietrich J (2007) Induction of CD8 T cells against a novel epitope in TB10.4: correlation with mycobacterial virulence and the presence of a functional region of difference-1. J Immunol 179: 3973–3981. 17785835

17. Tully G, Kortsik C, Höhn H, Zehbe I, Hitzler WE, et al. (2005) Highly focused T cell responses in latent human pulmonary Mycobacterium tuberculosis infection. J Immunol 174: 2174–2184. 15699149

18. Du G, Chen CY, Shen Y, Qiu L, Huang D, et al. (2010) TCR repertoire, clonal dominance, and pulmonary trafficking of mycobacterium-specific CD4+ and CD8+ T effector cells in immunity against tuberculosis. The Journal of Immunology 185: 3940–3947. doi: 10.4049/jimmunol.1001222 20805423

19. Luo W, Su J, Zhang X-B, Yang Z, Zhou M-Q, et al. (2012) Limited T cell receptor repertoire diversity in tuberculosis patients correlates with clinical severity. PLoS ONE 7: e48117. doi: 10.1371/journal.pone.0048117 23110186

20. Jacobsen M, Detjen AK, Mueller H, Gutschmidt A, Leitner S, et al. (2007) Clonal expansion of CD8+ effector T cells in childhood tuberculosis. J Immunol 179: 1331–1339. 17617626

21. Woodworth JS, Wu Y, Behar SM (2008) Mycobacterium tuberculosis-specific CD8+ T cells require perforin to kill target cells and provide protection in vivo. JImmunol 181: 8595–8603. 19050279

22. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, et al. (2007) Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27: 203–213. 17707129

23. Li H, Ye C, Ji G, Han J (2012) Determinants of public T cell responses. Cell research 22: 33–42. doi: 10.1038/cr.2012.1 22212481

24. Correia-Neves M, Waltzinger C, Mathis D, Benoist C (2001) The shaping of the T cell repertoire. Immunity 14: 21–32. 11163227

25. Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM (2002) Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity. Infection and Immunity 70: 4501–4509. 12117962

26. Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, et al. (2008) Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J ExpMed 205: 105–115. 18158321

27. Gallegos AM, Pamer EG, Glickman MS (2008) Delayed protection by ESAT-6-specific effector CD4+ T cells after airborne M. tuberculosis infection. J Exp Med 205: 2359–2368. doi: 10.1084/jem.20080353 18779346

28. Reiley WW, Calayag MD, Wittmer ST, Huntington JL, Pearl JE, et al. (2008) ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes. ProcNatlAcadSciUSA 105: 10961–10966. doi: 10.1073/pnas.0801496105 18667699

29. Ji H, Liu Y, Zhang Y, Shen XD, Gao F, et al. (2014) T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology.

30. Lee J, Su EW, Zhu C, Hainline S, Phuah J, et al. (2011) Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol 31: 3963–3974. doi: 10.1128/MCB.05297-11 21807895

31. Li H, Wu K, Tao K, Chen L, Zheng Q, et al. (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56: 1342–1351. doi: 10.1002/hep.25777 22505239

32. Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, et al. (2012) Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis 54: 784–791. doi: 10.1093/cid/cir951 22267721

33. Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, et al. (2014) Diversity and clonal selection in the human T-cell repertoire. Proceedings of the National Academy of Sciences 111: 13139–13144. doi: 10.1073/pnas.1409155111 25157137

34. Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R (2004) ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol 12: 500–508. 15488391

35. Majlessi L, Brodin P, Brosch R, Rojas MJ, Khun H, et al. (2005) Influence of ESAT-6 secretion system 1 (RD1) of Mycobacterium tuberculosis on the interaction between mycobacteria and the host immune system. The Journal of Immunology 174: 3570–3579. 15749894

36. Woodworth JS, Fortune SM, Behar SM (2008) Bacterial protein secretion is required for priming of CD8+ T cells specific for the Mycobacterium tuberculosis antigen CFP10. Infect Immun 76: 4199–4205. doi: 10.1128/IAI.00307-08 18591224

37. Baena A, Porcelli S (2009) Evasion and subversion of antigen presentation by Mycobacterium tuberculosis. Tissue Antigens 74: 189–204. doi: 10.1111/j.1399-0039.2009.01301.x 19563525

38. Comas I, Chakravartti J, Small PM, Galagan J, Niemann S, et al. (2010) Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. NatGenet 42: 498–503. doi: 10.1038/ng.590 20495566

39. Lindenstrom T, Aagaard C, Christensen D, Agger EM, Andersen P (2014) High-frequency vaccine-induced CD8(+) T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection. Eur J Immunol 44: 1699–1709. doi: 10.1002/eji.201344358 24677089

40. Aagaard CS, Hoang TTKT, Vingsbo-Lundberg C, Dietrich J, Andersen P (2009) Quality and vaccine efficacy of CD4+ T cell responses directed to dominant and subdominant epitopes in ESAT-6 from Mycobacterium tuberculosis. J Immunol 183: 2659–2668. doi: 10.4049/jimmunol.0900947 19620314

41. Woodworth JS, Aagaard CS, Hansen PR, Cassidy JP, Agger EM, et al. (2014) Protective CD4 T cells targeting cryptic epitopes of Mycobacterium tuberculosis resist infection-driven terminal differentiation. J Immunol 192: 3247–3258. doi: 10.4049/jimmunol.1300283 24574499

42. Yang J, He J, Huang H, Ji Z, Wei L, et al. (2013) Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection. BMC Infect Dis 13: 423. doi: 10.1186/1471-2334-13-423 24010943

43. Yang J, Xu K, Zheng J, Wei L, Fan J, et al. (2013) Limited T cell receptor beta variable repertoire responses to ESAT-6 and CFP-10 in subjects infected with Mycobacterium tuberculosis. Tuberculosis (Edinb) 93: 529–537. doi: 10.1016/j.tube.2013.05.007 23845455

44. Barry CE, Boshoff HI, Dartois V, Dick T, Ehrt S, et al. (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7: 845–855. doi: 10.1038/nrmicro2236 19855401

45. Lin PL, Rodgers M, Smith L, Bigbee M, Myers A, et al. (2009) Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77: 4631–4642. doi: 10.1128/IAI.00592-09 19620341

46. Nunes-Alves C, Booty MG, Carpenter SM, Jayaraman P, Rothchild AC, et al. (2014) In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol 12: 289–299. doi: 10.1038/nrmicro3230 24590243

47. Gorman JV, Starbeck-Miller G, Pham NL, Traver GL, Rothman PB, et al. (2014) Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol 192: 3133–3142. doi: 10.4049/jimmunol.1302290 24567532

48. Lewinsohn DA, Winata E, Swarbrick GM, Tanner KE, Cook MS, et al. (2007) Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B. PLoS Pathogens 3: e127–1249. 17677004

49. Lewinsohn DM, Swarbrick GM, Cansler ME, Null MD, Rajaraman V, et al. (2013) Human Mycobacterium tuberculosis CD8 T Cell Antigens/Epitopes Identified by a Proteomic Peptide Library. PLoS ONE 8: e67016. 23805289

50. Lindestam Arlehamn CS, Gerasimova A, Mele F, Henderson R, Swann J, et al. (2013) Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset. PLoS Pathogens 9: e1003130. doi: 10.1371/journal.ppat.1003130 23358848

51. Lepore M, Kalinicenko A, Colone A, Paleja B, Singhal A, et al. (2014) Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRbeta repertoire. Nat Commun 5: 3866. doi: 10.1038/ncomms4866 24832684

52. Stewart JJ, Lee CY, Ibrahim S, Watts P, Shlomchik M, et al. (1997) A Shannon entropy analysis of immunoglobulin and T cell receptor. Mol Immunol 34: 1067–1082. 9519765

53. Sherwood AM, Emerson RO, Scherer D, Habermann N, Buck K, et al. (2013) Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunol Immunother 62: 1453–1461. doi: 10.1007/s00262-013-1446-2 23771160

54. Moon JJ, Chu HH, Hataye J, Pagán AJ, Pepper M, et al. (2009) Tracking epitope-specific T cells. Nat Protoc 4: 565–581. doi: 10.1038/nprot.2009.9 19373228

55. Holst J, Vignali KM, Burton AR, Vignali DAA (2006) Rapid analysis of T-cell selection in vivo using T cell-receptor retrogenic mice. Nat Methods 3: 191–197. 16489336

56. Holst J, Szymczak-Workman AL, Vignali KM, Burton AR, Workman CJ, et al. (2006) Generation of T-cell receptor retrogenic mice. Nat Protoc 1: 406–417. 17406263

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 5
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa