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The precursors of memory: models and controversies

Nature Reviews Immunology volume 9, pages 662–668 (2009)Cite this article

Abstract

The adaptive immune system has evolved a unique capacity to remember a pathogen through the generation of memory T cells, which rapidly protect the host in the event of reinfection. How memory T cells develop and the relationship between effector and memory T cells has been actively debated in the literature for many years and several models have been proposed to explain the divergent developmental fates of T cell progeny. Here, Nature Reviews Immunology asks four leading researchers in the field to provide their thoughts and opinions on the ontogeny of memory T cells and its implications for vaccine design.

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Figure 1: Possible models of memory T cell differentiation.

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References

  1. Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  2. 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  PubMed  PubMed Central  Google Scholar 

  3. Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Bannard, O., Kraman, M. & Fearon. D. T. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 323, 505–509 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harrington, L. E., Janowski, K. M., Oliver, J. R., Zajac, A. J. & Weaver, C. T. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 452, 356–360 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Voehringer, D. et al. Viral infections induce abundant numbers of senescent CD8 T cells. J. Immunol. 167, 4838–4843 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Heffner, M. & Fearon, D. T. Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte. Proc. Natl Acad. Sci. USA 10, 13414–13419 (2007).

    Article  Google Scholar 

  9. Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nature Immunol. 4, 225–234 (2003).

    Article  CAS  Google Scholar 

  10. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Sarkar, S. et al. Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J. Immunol. 179, 6704–6714 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Miller, J. D. et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28, 710–722 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Lacombe, M. H., Hardy, M. P., Rooney, J. & Labrecque, N. IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization. J. Immunol. 175, 4400–4407 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Sun, J. C., Lehar, S. M. & Bevan, M. J. Augmented IL-7 signaling during viral infection drives greater expansion of effector T cells but does not enhance memory. J. Immunol. 177, 4458–4463 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Hand, T. W., Morre, M. & Kaech, S. M. Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc. Natl Acad. Sci. USA 104, 11730–11735 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Haring, J. S. et al. Constitutive expression of IL-7 receptor α does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J. Immunol. 180, 2855–2862 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Williams, M. A., Tyznik, A. J. & Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Prlic, M., Hernandez-Hoyos, G. & Bevan, M. J. Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response. J. Exp. Med. 203, 2135–2143 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zehn, D., Lee, S. Y. & Bevan, M. J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Prlic, M. & Bevan, M. J. Exploring regulatory mechanisms of CD8+ T cell contraction. Proc. Natl Acad. Sci. USA 105, 16689–16694 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Sallusto, F., Lenig, D., Förster, 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  PubMed  Google Scholar 

  24. Unsoeld, H., Krautwald, S., Voehringer, D., Kunzendorf, U. & Pircher, H. Cutting edge: CCR7+ and CCR7− memory T cells do not differ in immediate effector cell function. J. Immunol. 169, 638–641 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. 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  PubMed  PubMed Central  Google Scholar 

  27. Mescher, M. F. et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211, 81–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lau, L. L., Jamieson, B. D., Somasundaram, T. & Ahmed, R. Cytotoxic T-cell memory without antigen. Nature 369, 648–652 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Hou, S., Hyland, L., Ryan, K. W., Portner, A. & Doherty, P. C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652–654 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. 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  PubMed  Google Scholar 

  32. Murali-Krishna, K. et al. Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 286, 1377–1381 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Precopio, M. L. et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 204, 1405–1416 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. & Ahmed, R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 176, 2079–2083 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Kassiotis, G. & Stockinger, B. Anatomical heterogeneity of memory CD4+ T cells due to reversible adaptation to the microenvironment. J. Immunol. 173, 7292–7298 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Cauley, L. S. et al. Cutting edge: virus-specific CD4+ memory T cells in nonlymphoid tissues express a highly activated phenotype. J. Immunol. 169, 6655–6658 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Jacob, J. & Baltimore, D. Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399, 593–597 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Lefrançois, L. & Masopust, D. The road not taken: memory T cell fate 'decisions'. Nature Immunol. 10, 369–370 (2009).

    Article  Google Scholar 

  41. Teixeiro, E. et al. Different T cell receptor signals determine CD8+ memory versus effector development. Science 323, 502–505 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Opferman, J. T., Ober, B. T. & Ashton-Rickardt, P. G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Lauvau, G. et al. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 294, 1735–1739 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Jameson, S. C. T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin. Immunol. 17, 231–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Murali-Krishna, K. & Ahmed, R. Cutting edge: naive T cells masquerading as memory cells. J. Immunol. 165, 1733–1737 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Badovinac, V. P., Porter, B. B. & Harty, J. T. CD8+ T cell contraction is controlled by early inflammation. Nature Immunol. 5, 809–817 (2004).

    Article  CAS  Google Scholar 

  48. Hamilton, S. E., Wolkers, M. C., Schoenberger, S. P. & Jameson, S. C. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nature Immunol. 7, 475–481 (2006).

    Article  CAS  Google Scholar 

  49. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fuentealba, L. C., Eivers, E., Geissert, D., Taelman, V. & De Robertis, E. M. Asymmetric mitosis: unequal segregation of proteins destined for degradation. Proc. Natl Acad. Sci. USA 105, 7732–7737 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bouneaud, C., Garcia, Z., Kourilsky, P. & Pannetier, C. Lineage relationships, homeostasis, and recall capacities of central- and effector-memory CD8 T cells in vivo. J. Exp. Med. 201, 579–590 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bachmann, M. F., Wolint, P., Schwarz, K., Jäger, P. & Oxenius, A. Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor α and CD62L. J. Immunol. 175, 4686–4696 (2005).

    CAS  PubMed  Google Scholar 

  54. Lefrançois, L. & Puddington, L. Intestinal and pulmonary mucosal T cells: local heroes fight to maintain the status quo. Annu. Rev. Immunol. 24, 681–704 (2006).

    Article  PubMed  Google Scholar 

  55. Wakim, L. M., Waithman, J., van Rooijen, N., Heath, W. R. & Carbone, F. R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Obar, J. J., Fuse, S., Leung, E. K., Bellfy, S. C. & Usherwood, E. J. Gammaherpesvirus persistence alters key CD8 T-cell memory characteristics and enhances antiviral protection. J. Virol. 80, 8303–8315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vezys, V. et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 203, 2263–2269 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Rafi Ahmed is at the Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, USA. rahmed@emory.edu,

    Rafi Ahmed

  2. Bevan is at the Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195-7370, USA. mbevan@u.washington.ed,

    Michael J. Bevan

  3. Reiner is at the Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA. sreiner@mail.med.upenn.edu,

    Steven L. Reiner

  4. Department of Medicine, Douglas T. Fearon is at the Wellcome Trust Immunology Unit, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK. dtf1000@cam.ac.uk,

    Douglas T. Fearon

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  4. Douglas T. Fearon
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FURTHER INFORMATION

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Glossary

Central memory T (TCM) cell

A memory T cell that expresses CD62L and CCR7, can circulate from the blood to secondary lymphoid organs and maintains the ability for secondary proliferation.

Effector T cell

A CD4+ effector T cell secretes cytokines, such as interferon-γ, interleukin-4 (IL-4) or IL-17 and provides help for B cells. A CD8+ effector T cell can be characterized by granzyme B synthesis and target-cell killing.

Effector memory T (TEM) cell

A memory T cell that does not express CD62L or CCR7 and is unlikely to divide in response to a secondary infection, but produces perforin and granzyme B and can migrate to sites of inflammation, such as the skin and gut.

Memory T cell

A long-lived antigen-specific T cell that, following exposure to antigen, remains in the host in a less than mature state. Following a second exposure to the antigen a memory T cell mounts a more effective immune response than a naive antigen-specific T cell.

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Ahmed, R., Bevan, M., Reiner, S. et al. The precursors of memory: models and controversies. Nat Rev Immunol 9, 662–668 (2009). https://doi.org/10.1038/nri2619

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