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Functionally Diverse Subsets in CD4 T Cell Responses Against Influenza

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Abstract

Background

Antibody alone cannot provide optimal protection against many infectious diseases impacting global heath. In these cases, our challenge is to develop innovative vaccines that generate protective populations of memory T cells. However, our studies suggest that current paradigms explaining how memory CD4 T cells provide protection are inadequate. This is likely due to both the paucity of and heterogeneity of memory CD4 T cells observed in vivo, which make analysis extremely difficult.

Summary

Here, we discuss new findings that indicate there is extensive functional heterogeneity within effector and memory CD4 T cell populations both in vivo and in vitro. Using influenza as an example, we also discuss the merits of employing reductionist approaches to explore how unique subsets of CD4 T cells are generated, what mechanisms of protection they use, and where they stand on the axes of differentiation that define T cell subsets.

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References

  1. Dutton RW, Swain SL, Woodland DL. Vaccines against pandemic influenza. Viral Immunol. 2007;20:326–7. doi:10.1089/vim.2007.0011.

    Article  PubMed  CAS  Google Scholar 

  2. Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003;4:835–42. doi:10.1038/ni969.

    Article  PubMed  CAS  Google Scholar 

  3. Stockinger B, Bourgeois C, Kassiotis G. CD4+ memory T cells: functional differentiation and homeostasis. Immunol Rev. 2006;211:39–48. doi:10.1111/j.0105-2896.2006.00381.x.

    Article  PubMed  CAS  Google Scholar 

  4. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–73. doi:10.1146/annurev.iy.07.040189.001045.

    Article  PubMed  CAS  Google Scholar 

  5. Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008;8:337–48. doi:10.1038/nri2295.

    Article  PubMed  CAS  Google Scholar 

  6. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008;453:1051–7. doi:10.1038/nature07036.

    Article  PubMed  CAS  Google Scholar 

  7. King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 2008;26:741–66. doi:10.1146/annurev.immunol.26.021607.090344.

    Article  PubMed  CAS  Google Scholar 

  8. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, Locksley RM, Haynes L, Randall TD, Cooper AM. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8:369–77. doi:10.1038/ni1449.

    Article  PubMed  CAS  Google Scholar 

  9. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006;25:195–201. doi:10.1016/j.immuni.2006.08.003.

    Article  PubMed  CAS  Google Scholar 

  10. Kelso A, Groves P, Ramm L, Doyle AG. Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations. Int Immunol. 1999;11:617–21. doi:10.1093/intimm/11.4.617.

    Article  PubMed  CAS  Google Scholar 

  11. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63. doi:10.1146/annurev.immunol.22.012703.104702.

    Article  PubMed  CAS  Google Scholar 

  12. Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, McHeyzer-Williams LJ, McHeyzer-Williams MG. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat Immunol. 2007;8:753–61. doi:10.1038/ni1472.

    Article  PubMed  CAS  Google Scholar 

  13. Swain SL, Croft M, Dubey C, Haynes L, Rogers P, Zhang X, Bradley LM. From naive to memory T cells. Immunol Rev. 1996;150:143–67. doi:10.1111/j.1600-065X.1996.tb00700.x.

    Article  PubMed  CAS  Google Scholar 

  14. Dutton RW, Bradley LM, Swain SL. T cell memory. Annu Rev Immunol. 1998;16:201–23. doi:10.1146/annurev.immunol.16.1.201.

    Article  PubMed  CAS  Google Scholar 

  15. Agrewala JN, Brown DM, Lepak NM, Duso D, Huston G, Swain SL. Unique ability of activated CD4+ T cells but not rested effectors to migrate to non-lymphoid sites in the absence of inflammation. J Biol Chem. 2007;282:6106–15. doi:10.1074/jbc.M608266200.

    Article  PubMed  CAS  Google Scholar 

  16. Bradley LM, Haynes L, Swain SL. IL-7: maintaining T-cell memory and achieving homeostasis. Trends Immunol. 2005;26:172–6. doi:10.1016/j.it.2005.01.004.

    Article  PubMed  CAS  Google Scholar 

  17. Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunol Rev. 2006;211:154–63. doi:10.1111/j.0105-2896.2006.00401.x.

    Article  PubMed  CAS  Google Scholar 

  18. Bradley LM, Duncan DD, Yoshimoto K, Swain SL. Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen. J Immunol. 1993;150:3119–30.

    PubMed  CAS  Google Scholar 

  19. Swain SL, Agrewala JN, Brown DM, Jelley-Gibbs DM, Golech S, Huston G, Jones SC, Kamperschroer C, Lee WH, McKinstry KK, Roman E, Strutt T, Weng NP. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev. 2006;211:8–22. doi:10.1111/j.0105-2896.2006.00388.x.

    Article  PubMed  CAS  Google Scholar 

  20. Roman E, Miller E, Harmsen A, Wiley J, Von Andrian UH, Huston G, Swain SL. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function. J Exp Med. 2002;196:957–68. doi:10.1084/jem.20021052.

    Article  PubMed  CAS  Google Scholar 

  21. Brown DM, Dilzer AM, Meents DL, Swain SL. CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol. 2006;177:2888–98.

    PubMed  CAS  Google Scholar 

  22. Kamperschroer C, Roberts DM, Zhang Y, Weng NP, Swain SL. SAP enables T cells to help B cells by a mechanism distinct from Th cell programming or CD40 ligand regulation. J Immunol. 2008;181:3994–4003.

    PubMed  CAS  Google Scholar 

  23. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453:236–40. doi:10.1038/nature06878.

    Article  PubMed  CAS  Google Scholar 

  24. McKinstry KK, Strutt TM, Swain SL. The effector to memory transition of CD4 T cells. Immunol Res. 2008;40:114–27. doi:10.1007/s12026-007-8004-y.

    Article  PubMed  CAS  Google Scholar 

  25. Jelley-Gibbs DM, Brown DM, Dibble JP, Haynes L, Eaton SM, Swain SL. Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med. 2005;202:697–706. doi:10.1084/jem.20050227.

    Article  PubMed  CAS  Google Scholar 

  26. Jelley-Gibbs DM, Dibble JP, Brown DM, Strutt TM, McKinstry KK, Swain SL. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J Immunol. 2007;178:7563–70.

    PubMed  CAS  Google Scholar 

  27. Jelley-Gibbs DM, Strutt TM, McKinstry KK, Swain SL. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunol Cell Biol. 2008;86:343–52. doi:10.1038/icb.2008.13.

    Article  PubMed  CAS  Google Scholar 

  28. Catron DM, Rusch LK, Hataye J, Itano AA, Jenkins MK. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J Exp Med. 2006;203:1045–54. doi:10.1084/jem.20051954.

    Article  PubMed  CAS  Google Scholar 

  29. Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body. Nature 2001;410:101–5. doi:10.1038/35065111.

    Article  PubMed  CAS  Google Scholar 

  30. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, Longworth SA, Vinup KE, Mrass P, Oliaro J, Killeen N, Orange JS, Russell SM, Weninger W, Reiner SL. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 2007;315:1687–91. doi:10.1126/science.1139393.

    Article  PubMed  CAS  Google Scholar 

  31. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol. 2002;2:251–62. doi:10.1038/nri778.

    Article  PubMed  CAS  Google Scholar 

  32. Hu H, Huston G, Duso D, Lepak N, Roman E, Swain SL. CD4(+) T cell effectors can become memory cells with high efficiency and without further division. Nat Immunol. 2001;2:705–10. doi:10.1038/90643.

    Article  PubMed  CAS  Google Scholar 

  33. Harrington LE, Janowski KM, Oliver JR, Zajac AJ, Weaver CT. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 2008;452:356–60.

    Article  PubMed  CAS  Google Scholar 

  34. Lohning M, Hegazy AN, Pinschewer DD, Busse D, Lang KS, Hofer T, Radbruch A, Zinkernagel RM, Hengartner H. Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J Exp Med. 2008;205:53–61. doi:10.1084/jem.20071855.

    Article  PubMed  CAS  Google Scholar 

  35. McKinstry KK, Golech S, Lee WH, Huston G, Weng NP, Swain SL. Rapid default transition of CD4 T cell effectors to functional memory cells. J Exp Med. 2007;204:2199–211.

    Article  PubMed  CAS  Google Scholar 

  36. Wu CY, Kirman JR, Rotte MJ, Davey DF, Perfetto SP, Rhee EG, Freidag BL, Hill BJ, Douek DC, Seder RA. Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo. Nat Immunol. 2002;3:852–8. doi:10.1038/ni832.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by P01AI04630, P01AI45666, and R56AI967294 and the Trudeau Institute.

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Authors and Affiliations

  1. Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY, 12983, USA

    Tara M. Strutt, K. Kai McKinstry & Susan L. Swain

Authors
  1. Tara M. Strutt
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  2. K. Kai McKinstry
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  3. Susan L. Swain
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Correspondence to Tara M. Strutt.

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Strutt, T.M., McKinstry, K.K. & Swain, S.L. Functionally Diverse Subsets in CD4 T Cell Responses Against Influenza. J Clin Immunol 29, 145–150 (2009). https://doi.org/10.1007/s10875-008-9266-4

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  • DOI: https://doi.org/10.1007/s10875-008-9266-4

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