Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection


Following infection or vaccination, memory CD8 T cells persist at higher numbers and have enhanced functional abilities compared to naïve cells, providing immune hosts with increased protection from viral, bacterial, or parasitic infection. Protection provided by memory CD8 T cells depends on the numbers, quality (functional abilities), and location of cells present at the time of re-infection. While memory CD8 T cells can be maintained for great lengths of time, how time influences qualitative properties of these cells remains largely unknown. We show that the phenotype and functions of circulating memory CD8 T cells, including cytokine production, proliferation, and mitochondrial function following re-infection improves with time after infection. We also show that changes in function are not due solely to changes in subset composition of the memory pool. Importantly, due to enhanced proliferative and metabolic abilities, memory CD8 T cells analyzed late after infection were more protective against a chronic viral infection. Our study shows that the properties of memory CD8 T cells continue to change with time, and that the protective outcome of vaccination may depend on the timing of re-infection relative to the initial immunization.


Vyšlo v časopise: Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005219
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005219

Souhrn

Following infection or vaccination, memory CD8 T cells persist at higher numbers and have enhanced functional abilities compared to naïve cells, providing immune hosts with increased protection from viral, bacterial, or parasitic infection. Protection provided by memory CD8 T cells depends on the numbers, quality (functional abilities), and location of cells present at the time of re-infection. While memory CD8 T cells can be maintained for great lengths of time, how time influences qualitative properties of these cells remains largely unknown. We show that the phenotype and functions of circulating memory CD8 T cells, including cytokine production, proliferation, and mitochondrial function following re-infection improves with time after infection. We also show that changes in function are not due solely to changes in subset composition of the memory pool. Importantly, due to enhanced proliferative and metabolic abilities, memory CD8 T cells analyzed late after infection were more protective against a chronic viral infection. Our study shows that the properties of memory CD8 T cells continue to change with time, and that the protective outcome of vaccination may depend on the timing of re-infection relative to the initial immunization.


Zdroje

1. Harty JT, Badovinac VP (2008) Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 8: 107–119. doi: 10.1038/nri2251 18219309

2. Carbone FR, Mackay LK, Heath WR, Gebhardt T (2013) Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr Opin Immunol 25: 329–333. doi: 10.1016/j.coi.2013.05.007 23746791

3. Harty JT, Tvinnereim AR, White DW (2000) CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol 18: 275–308. 10837060

4. Jameson SC, Masopust D (2009) Diversity in T cell memory: an embarrassment of riches. Immunity 31: 859–871. doi: 10.1016/j.immuni.2009.11.007 20064446

5. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401: 708–712. 10537110

6. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, et al. (2003) Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 4: 225–234. 12563257

7. Schenkel JM, Masopust D (2014) Tissue-resident memory T cells. Immunity 41: 886–897. doi: 10.1016/j.immuni.2014.12.007 25526304

8. Bachmann MF, Wolint P, Schwarz K, Jager P, Oxenius A (2005) Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor alpha and CD62L. J Immunol 175: 4686–4696. 16177116

9. 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

10. Nolz JC, Harty JT (2011) Protective capacity of memory CD8+ T cells is dictated by antigen exposure history and nature of the infection. Immunity 34: 781–793. doi: 10.1016/j.immuni.2011.03.020 21549619

11. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, et al. (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10: 524–530. doi: 10.1038/ni.1718 19305395

12. Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, et al. (2012) Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483: 227–231. doi: 10.1038/nature10851 22388819

13. Schenkel JM, Fraser KA, Vezys V, Masopust D (2013) Sensing and alarm function of resident memory CD8(+) T cells. Nat Immunol 14: 509–513. doi: 10.1038/ni.2568 23542740

14. Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, et al. (2014) T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346: 98–101. doi: 10.1126/science.1254536 25170049

15. Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, et al. (2012) Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci U S A 109: 7037–7042. doi: 10.1073/pnas.1202288109 22509047

16. Kaufman DR, Liu J, Carville A, Mansfield KG, Havenga MJ, et al. (2008) Trafficking of antigen-specific CD8+ T lymphocytes to mucosal surfaces following intramuscular vaccination. J Immunol 181: 4188–4198. 18768876

17. Wu T, Hu Y, Lee YT, Bouchard KR, Benechet A, et al. (2014) Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Biol 95: 215–224. doi: 10.1189/jlb.0313180 24006506

18. Homann D, Teyton L, Oldstone MB (2001) Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med 7: 913–919. 11479623

19. Ahmed R, Akondy RS (2011) Insights into human CD8(+) T-cell memory using the yellow fever and smallpox vaccines. Immunol Cell Biol 89: 340–345. doi: 10.1038/icb.2010.155 21301482

20. Demkowicz WE Jr., Littaua RA, Wang J, Ennis FA (1996) Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J Virol 70: 2627–2631. 8642697

21. Hammarlund E, Lewis MW, Hanifin JM, Mori M, Koudelka CW, et al. (2010) Antiviral immunity following smallpox virus infection: a case-control study. J Virol 84: 12754–12760. doi: 10.1128/JVI.01763-10 20926574

22. Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, et al. (2003) Duration of antiviral immunity after smallpox vaccination. Nat Med 9: 1131–1137. 12925846

23. Naniche D, Garenne M, Rae C, Manchester M, Buchta R, et al. (2004) Decrease in measles virus-specific CD4 T cell memory in vaccinated subjects. J Infect Dis 190: 1387–1395. 15378430

24. Sarkar S, Teichgraber V, Kalia V, Polley A, Masopust D, et al. (2007) Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J Immunol 179: 6704–6714. 17982060

25. Jabbari A, Harty JT (2006) Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype. J Exp Med 203: 919–932. 16567385

26. Roberts AD, Ely KH, Woodland DL (2005) Differential contributions of central and effector memory T cells to recall responses. J Exp Med 202: 123–133. 15983064

27. Martin MD, Condotta SA, Harty JT, Badovinac VP (2012) Population dynamics of naive and memory CD8 T cell responses after antigen stimulations in vivo. J Immunol 188: 1255–1265. doi: 10.4049/jimmunol.1101579 22205031

28. Masopust D, Ha SJ, Vezys V, Ahmed R (2006) Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J Immunol 177: 831–839. 16818737

29. Schmidt NW, Butler NS, Badovinac VP, Harty JT (2010) Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. PLoS Pathog 6: e1000998. doi: 10.1371/journal.ppat.1000998 20657824

30. Schmidt NW, Podyminogin RL, Butler NS, Badovinac VP, Tucker BJ, et al. (2008) Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria. Proc Natl Acad Sci U S A 105: 14017–14022. doi: 10.1073/pnas.0805452105 18780790

31. Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, et al. (2013) Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341: 1359–1365. doi: 10.1126/science.1241800 23929949

32. Woodland DL (2004) Jump-starting the immune system: prime-boosting comes of age. Trends Immunol 25: 98–104. 15102369

33. Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L (2002) Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168: 4827–4831. 11994430

34. Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R, et al. (2002) Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 195: 1541–1548. 12070282

35. Goldrath AW, Sivakumar PV, Glaccum M, Kennedy MK, Bevan MJ, et al. (2002) Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med 195: 1515–1522. 12070279

36. Badovinac VP, Messingham KA, Hamilton SE, Harty JT (2003) Regulation of CD8+ T cells undergoing primary and secondary responses to infection in the same host. J Immunol 170: 4933–4942. 12734336

37. Nolz JC, Rai D, Badovinac VP, Harty JT (2012) Division-linked generation of death-intermediates regulates the numerical stability of memory CD8 T cells. Proc Natl Acad Sci U S A 109: 6199–6204. doi: 10.1073/pnas.1118868109 22474367

38. Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57. doi: 10.1038/nprot.2008.211 19131956

39. Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, et al. (2006) From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34: D354–357. 16381885

40. MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31: 259–283. doi: 10.1146/annurev-immunol-032712-095956 23298210

41. Chang JT, Wherry EJ, Goldrath AW (2014) Molecular regulation of effector and memory T cell differentiation. Nat Immunol 15: 1104–1115. doi: 10.1038/ni.3031 25396352

42. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, et al. (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35: 871–882. doi: 10.1016/j.immuni.2011.09.021 22195744

43. Wang R, Green DR (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13: 907–915. doi: 10.1038/ni.2386 22990888

44. Pearce EL, Poffenberger MC, Chang CH, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342: 1242454. doi: 10.1126/science.1242454 24115444

45. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, et al. (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460: 103–107. doi: 10.1038/nature08097 19494812

46. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, et al. (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36: 68–78. doi: 10.1016/j.immuni.2011.12.007 22206904

47. O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, et al. (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41: 75–88. doi: 10.1016/j.immuni.2014.06.005 25001241

48. Kaech SM, Hemby S, Kersh E, Ahmed R (2002) Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111: 837–851. 12526810

49. Best JA, Blair DA, Knell J, Yang E, Mayya V, et al. (2013) Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat Immunol 14: 404–412. doi: 10.1038/ni.2536 23396170

50. Russ BE, Olshanksy M, Smallwood HS, Li J, Denton AE, et al. (2014) Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8(+) T cell differentiation. Immunity 41: 853–865. doi: 10.1016/j.immuni.2014.11.001 25517617

51. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545–15550. 16199517

52. Ma A, Koka R, Burkett P (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24: 657–679. 16551262

53. Slutter B, Pewe LL, Kaech SM, Harty JT (2013) Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus. Immunity 39: 939–948. doi: 10.1016/j.immuni.2013.09.013 24238342

54. Fraser KA, Schenkel JM, Jameson SC, Vezys V, Masopust D (2013) Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 39: 171–183. doi: 10.1016/j.immuni.2013.07.003 23890070

55. van der Windt GJ, O'Sullivan D, Everts B, Huang SC, Buck MD, et al. (2013) CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci U S A 110: 14336–14341. doi: 10.1073/pnas.1221740110 23940348

56. Seder RA, Darrah PA, Roederer M (2008) T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 8: 247–258. doi: 10.1038/nri2274 18323851

57. Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291: 2413–2417. 11264538

58. Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, et al. (2012) Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol 188: 4866–4875. doi: 10.4049/jimmunol.1200402 22504644

59. Schenkel JM, Fraser KA, Masopust D (2014) Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs. J Immunol 192: 2961–2964. doi: 10.4049/jimmunol.1400003 24600038

60. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, et al. (2005) Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 6: 1236–1244. 16273099

61. Banerjee A, Gordon SM, Intlekofer AM, Paley MA, Mooney EC, et al. (2010) Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 185: 4988–4992. doi: 10.4049/jimmunol.1002042 20935204

62. Zhou X, Yu S, Zhao DM, Harty JT, Badovinac VP, et al. (2010) Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. Immunity 33: 229–240. doi: 10.1016/j.immuni.2010.08.002 20727791

63. Badovinac VP, Haring JS, Harty JT (2007) Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection. Immunity 26: 827–841. 17555991

64. Wirth TC, Pham NL, Harty JT, Badovinac VP (2009) High initial frequency of TCR-transgenic CD8 T cells alters inflammation and pathogen clearance without affecting memory T cell function. Mol Immunol 47: 71–78. doi: 10.1016/j.molimm.2008.12.018 19195704

65. Mueller SN, Langley WA, Li G, Garcia-Sastre A, Webby RJ, et al. (2010) Qualitatively different memory CD8+ T cells are generated after lymphocytic choriomeningitis virus and influenza virus infections. J Immunol 185: 2182–2190. doi: 10.4049/jimmunol.1001142 20639484

66. Obar JJ, Jellison ER, Sheridan BS, Blair DA, Pham QM, et al. (2011) Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol 187: 4967–4978. doi: 10.4049/jimmunol.1102335 21987662

67. Badovinac VP, Harty JT (2007) Manipulating the rate of memory CD8+ T cell generation after acute infection. J Immunol 179: 53–63. 17579021

68. Badovinac VP, Messingham KA, Jabbari A, Haring JS, Harty JT (2005) Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med 11: 748–756. 15951824

69. Pham NL, Badovinac VP, Harty JT (2009) A default pathway of memory CD8 T cell differentiation after dendritic cell immunization is deflected by encounter with inflammatory cytokines during antigen-driven proliferation. J Immunol 183: 2337–2348. doi: 10.4049/jimmunol.0901203 19635915

70. Stelekati E, Shin H, Doering TA, Dolfi DV, Ziegler CG, et al. (2014) Bystander chronic infection negatively impacts development of CD8(+) T cell memory. Immunity 40: 801–813. doi: 10.1016/j.immuni.2014.04.010 24837104

71. Wirth TC, Xue HH, Rai D, Sabel JT, Bair T, et al. (2010) Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8(+) T cell differentiation. Immunity 33: 128–140. doi: 10.1016/j.immuni.2010.06.014 20619696

72. Rai D, Martin MD, Badovinac VP (2014) The longevity of memory CD8 T cell responses after repetitive antigen stimulations. J Immunol 192: 5652–5659. doi: 10.4049/jimmunol.1301063 24829415

73. Martin MD, Badovinac VP (2014) Influence of time and number of antigen encounters on memory CD8 T cell development. Immunol Res 59: 35–44. doi: 10.1007/s12026-014-8522-3 24825776

74. Martin MD, Wirth TC, Lauer P, Harty JT, Badovinac VP (2011) The impact of pre-existing memory on differentiation of newly recruited naive CD8 T cells. J Immunol 187: 2923–2931. doi: 10.4049/jimmunol.1100698 21832161

75. Jabbari A, Harty JT (2006) Simultaneous assessment of antigen-stimulated cytokine production and memory subset composition of memory CD8 T cells. J Immunol Methods 313: 161–168. 16762359

76. Richer MJ, Nolz JC, Harty JT (2013) Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8(+) T cells by enhancing T cell receptor signaling. Immunity 38: 140–152. doi: 10.1016/j.immuni.2012.09.017 23260194

77. Haining WN, Wherry EJ (2010) Integrating genomic signatures for immunologic discovery. Immunity 32: 152–161. doi: 10.1016/j.immuni.2010.02.001 20189480

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
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