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Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells

Nature Immunology volume 11, pages 83–89 (2010)Cite this article

Abstract

We used a sensitive method based on tetramers of peptide and major histocompatibility complex II (pMHCII) to determine whether CD4+ memory T cells resemble the T helper type 1 (TH1) and interleukin 17 (IL-17)-producing T helper (TH17) subsets described in vitro. Intravenous or intranasal infection with Listeria monocytogenes induced pMHCII-specific CD4+ naive T cells to proliferate and produce effector cells, about 10% of which resembled TH1 or TH17 cells, respectively. TH1 cells were also present among the memory cells that survived 3 months after infection, whereas TH17 cells disappeared. The short lifespan of TH17 cells was associated with small amounts of the antiapoptotic protein Bcl-2, the IL-15 receptor and the receptor CD27, and little homeostatic proliferation. These results suggest that TH1 cells induced by intravenous infection are more efficient at entering the memory pool than are TH17 cells induced by intranasal infection.

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Figure 1: Infection with LM-2W1S induces the clonal expansion of 2W1S:I-Ab–specific memory cells.
Figure 2: The 2W1S:I-Ab–specific CD4+ memory T cells decay after infection with LM-2W1S.
Figure 3: Lymphokine production by 2W1S:I-Ab–specific CD4+ memory T cells.
Figure 4: Survival of IFN-γ- and IL-17A-producing 2W1S:I-Ab–specific CD4+ memory T cells.
Figure 5: Surface phenotype of 2W1S:I-Ab–specific T cells.
Figure 6: CD27− CD4+ memory T cells are short-lived.
Figure 7: CD4+ memory T cells undergo limited homeostatic proliferation.

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References

  1. Jenkins, M.K. et al. In vivo activation of antigen-specific CD4 T cells. Annu. Rev. Immunol. 19, 23–45 (2001).

    Article  CAS  Google Scholar 

  2. Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    Article  CAS  Google Scholar 

  5. Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

    Article  CAS  Google Scholar 

  6. Seder, R.A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat. Immunol. 4, 835–842 (2003).

    Article  CAS  Google Scholar 

  7. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  Google Scholar 

  8. Reiner, S.L. & Locksley, R.M. The regulation of immunity to Leishmania major. Annu. Rev. Immunol. 13, 151–177 (1995).

    Article  CAS  Google Scholar 

  9. Swain, S.L., Hu, H. & Huston, G. Class II-independent generation of CD4 memory T cells from effectors. Science 286, 1381–1383 (1999).

    Article  CAS  Google Scholar 

  10. Lohning, M. et al. Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J. Exp. Med. 205, 53–61 (2008).

    Article  CAS  Google Scholar 

  11. Li, J., Huston, G. & Swain, S.L. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J. Exp. Med. 198, 1807–1815 (2003).

    Article  CAS  Google Scholar 

  12. Hataye, J., Moon, J.J., Khoruts, A., Reilly, C. & Jenkins, M.K. Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 312, 114–116 (2006).

    Article  CAS  Google Scholar 

  13. Marzo, A.L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat. Immunol. 6, 793–799 (2005).

    Article  CAS  Google Scholar 

  14. Badovinac, V.P., Haring, J.S. & Harty, J.T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).

    Article  CAS  Google Scholar 

  15. Rees, W. et al. An inverse relationship between T cell receptor affinity and antigen dose during CD4+ T cell responses in vivo and in vitro. Proc. Natl. Acad. Sci. USA 96, 9781–9786 (1999).

    Article  CAS  Google Scholar 

  16. Moon, J.J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203–213 (2007).

    Article  CAS  Google Scholar 

  17. Ertelt, J.M. et al. Selective priming and expansion of antigen-specific Foxp3− CD4+ T cells during Listeria monocytogenes infection. J. Immunol. 182, 3032–3038 (2009).

    Article  CAS  Google Scholar 

  18. Muller, W.J. et al. Recombinant Listeria monocytogenes expressing an immunodominant peptide fails to protect after intravaginal challenge with herpes simplex virus-2. Arch. Virol. 153, 1165–1169 (2008).

    Article  CAS  Google Scholar 

  19. Portnoy, D.A., Auerbuch, V. & Glomski, I.J. The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. J. Cell Biol. 158, 409–414 (2002).

    Article  CAS  Google Scholar 

  20. Moon, J.J. et al. Tracking epitope-specific T cells. Nat. Protoc. 4, 565–581 (2009).

    Article  CAS  Google Scholar 

  21. Kaech, S.M., Hemby, S., Kersh, E. & Ahmed, R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837–851 (2002).

    Article  CAS  Google Scholar 

  22. Khoruts, A., Mondino, A., Pape, K.A., Reiner, S.L. & Jenkins, M.K. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J. Exp. Med. 187, 225–236 (1998).

    Article  CAS  Google Scholar 

  23. Pape, K.A., Merica, R., Mondino, A., Khoruts, A. & Jenkins, M.K. Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance. J. Immunol. 160, 4719–4729 (1998).

    CAS  PubMed  Google Scholar 

  24. Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  25. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

  26. Woolard, M.D., Hensley, L.L., Kawula, T.H. & Frelinger, J.A. Respiratory Francisella tularensis live vaccine strain infection induces Th17 cells and prostaglandin E2, which inhibits generation of γ interferon-positive T cells. Infect. Immun. 76, 2651–2659 (2008).

    Article  CAS  Google Scholar 

  27. Zhang, Z., Clarke, T.B. & Weiser, J.N. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J. Clin. Invest. 119, 1899–1909 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Park, H.S. et al. Primary induction of CD4 T cell responses in nasal associated lymphoid tissue during group A streptococcal infection. Eur. J. Immunol. 34, 2843–2853 (2004).

    Article  CAS  Google Scholar 

  29. Hikono, H. et al. Activation phenotype, rather than central- or effector-memory phenotype, predicts the recall efficacy of memory CD8+ T cells. J. Exp. Med. 204, 1625–1636 (2007).

    Article  CAS  Google Scholar 

  30. Snyder, C.M. et al. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29, 650–659 (2008).

    Article  CAS  Google Scholar 

  31. Hendriks, J. et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nat. Immunol. 1, 433–440 (2000).

    Article  CAS  Google Scholar 

  32. Hendriks, J., Xiao, Y. & Borst, J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369–1380 (2003).

    Article  CAS  Google Scholar 

  33. Dolfi, D.V. et al. Late signals from CD27 prevent Fas-dependent apoptosis of primary CD8+ T cells. J. Immunol. 180, 2912–2921 (2008).

    Article  CAS  Google Scholar 

  34. Rubinstein, M.P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl. Acad. Sci. USA 103, 9166–9171 (2006).

    Article  CAS  Google Scholar 

  35. Tokoyoda, K. et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30, 721–730 (2009).

    Article  CAS  Google Scholar 

  36. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  Google Scholar 

  37. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  Google Scholar 

  38. Sato, A. et al. CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. J. Immunol. 171, 3684–3690 (2003).

    Article  CAS  Google Scholar 

  39. Kelsall, B. Recent progress in understanding the phenotype and function of intestinal dendritic cells and macrophages. Mucosal Immunol. 1, 460–469 (2008).

    Article  CAS  Google Scholar 

  40. Reis e Sousa, C. et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med. 186, 1819–1829 (1997).

    Article  CAS  Google Scholar 

  41. Hsieh, C.S., Heimberger, A.B., Gold, J.S. & O'Garra, A. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1992).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Monack, D.M., Mueller, A. & Falkow, S. Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat. Rev. Microbiol. 2, 747–765 (2004).

    Article  CAS  Google Scholar 

  44. Surh, C.D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    Article  CAS  Google Scholar 

  45. Allam, A. et al. The CD8+ memory T-cell state of readiness is actively maintained and reversible. Blood 114, 2121–2130 (2009).

    Article  CAS  Google Scholar 

  46. Kraus, Z.J., Haring, J.S. & Bishop, G.A. TNF receptor-associated factor 5 is required for optimal T cell expansion and survival in response to infection. J. Immunol. 181, 7800–7809 (2008).

    Article  CAS  Google Scholar 

  47. Intlekofer, A.M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    Article  CAS  Google Scholar 

  48. Joshi, N.S. et al. 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 (2007).

    Article  CAS  Google Scholar 

  49. Soares, H. et al. A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12-independent but CD70-dependent mechanism in vivo. J. Exp. Med. 204, 1095–1106 (2007).

    Article  CAS  Google Scholar 

  50. Keller, A.M., Schildknecht, A., Xiao, Y., van den Broek, M. & Borst, J. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity 29, 934–946 (2008).

    Article  CAS  Google Scholar 

  51. van Oosterwijk, M.F. et al. CD27–CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell development. Int. Immunol. 19, 713–718 (2007).

    Article  CAS  Google Scholar 

  52. Yang, X.O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  Google Scholar 

  53. Ribot, J.C. et al. CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17-producing γδ T cell subsets. Nat. Immunol. 10, 427–436 (2009).

    Article  CAS  Google Scholar 

  54. Lu, Y.J. et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog. 4, e1000159 (2008).

    Article  Google Scholar 

  55. Yamanaka, N., Hotomi, M. & Billal, D.S. Clinical bacteriology and immunology in acute otitis media in children. J. Infect. Chemother. 14, 180–187 (2008).

    Article  Google Scholar 

  56. Stoklasek, T.A., Schluns, K.S. & Lefrancois, L. Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J. Immunol. 177, 6072–6080 (2006).

    Article  CAS  Google Scholar 

  57. Boggs, D.R. The total marrow mass of the mouse: a simplified method of measurement. Am. J. Hematol. 16, 277–286 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Jameson, H. Chu and J. Taylor for reviewing the manuscript; J. Walter, J. McLachlan and A. Schmidt for technical assistance; and P. Champoux and N. Shah for flow cytometry sorting. Supported by the US National Institutes of Health (AI39614, AI66016 and AI27998 to M.K.J.; T32-AI07313 to A.J.P.; and T32-CA9138 to M.P.).

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  1. Marion Pepper and Jonathan L Linehan: These authors contributed equally to this work.

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  1. Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    Marion Pepper, Jonathan L Linehan, Antonio J Pagán, Traci Zell, Thamotharampillai Dileepan, P Patrick Cleary & Marc K Jenkins

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Contributions

M.P. designed the study, did experiments, analyzed data and wrote the manuscript; J.L.L., A.J.P., T.Z. and T.D. did experiments; P.P.C. designed experiments; and M.K.J. designed the study, analyzed data and wrote the manuscript.

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Correspondence to Marc K Jenkins.

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Pepper, M., Linehan, J., Pagán, A. et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol 11, 83–89 (2010). https://doi.org/10.1038/ni.1826

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