Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspectives
  • Published:

Opinion-decision making in the immune system

Progressive differentiation and selection of the fittest in the immune response

Nature Reviews Immunology volume 2, pages 982–987 (2002)Cite this article

Abstract

T cells are stimulated by stochastic exposure to antigen-presenting cells and cytokines. We review evidence that the level of signal that is accumulated determines progression through hierarchical thresholds for proliferation and differentiation, leading to the generation of various intermediates and effector T cells. These cells are then selected to enter the memory pool according to their fitness — that is, their capacity to access and use survival signals. We suggest that the intermediates that are generated by antigenic stimulation of T and B cells persist as central memory cells, which can mount secondary responses to antigen and maintain appropriate levels of effector cells and antibodies throughout the lifetime of an individual.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Model of progressive differentiation and rescue of the fittest in the immune response.
Figure 2: Antigen-independent maintenance of protective T- and B-cell memory.

Similar content being viewed by others

References

  1. Lanzavecchia, A. & Sallusto, F. Dynamics of T-lymphocyte responses: intermediates, effectors and memory cells. Science 290, 92–97 (2000).

    Article  CAS  Google Scholar 

  2. Valitutti, S., Muller, S., Cella, M., Padovan, E. & Lanzavecchia, A. Serial triggering of many T-cell receptors by a few peptide–MHC complexes. Nature 375, 148–151 (1995).

    Article  CAS  Google Scholar 

  3. Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T-lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999).

    Article  CAS  Google Scholar 

  4. Porgador, A., Yewdell, J. W., Deng, Y., Bennink, J. R. & Germain, R. N. Localization, quantitation and in situ detection of specific peptide–MHC class I complexes using a monoclonal antibody. Immunity 6, 715–726 (1997).

    Article  CAS  Google Scholar 

  5. Dustin, M. L., Allen, P. M. & Shaw, A. S. Environmental control of immunological synapse formation and duration. Trends Immunol. 22, 192–194 (2001).

    Article  CAS  Google Scholar 

  6. Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T-cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).

    Article  Google Scholar 

  7. Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).

    Article  CAS  Google Scholar 

  8. Crabtree, G. R. Contingent genetic regulatory events in T-lymphocyte activation. Science 243, 355–361 (1989).

    Article  CAS  Google Scholar 

  9. Marrack, P. et al. Homeostasis of αβ TCR+ T cells. Nature Immunol. 1, 107–112 (2000).

    Article  CAS  Google Scholar 

  10. Kunkel, E. J. & Butcher, E. C. Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1–4 (2002).

    Article  CAS  Google Scholar 

  11. Lenardo, M. et al. Mature T-lymphocyte apoptosis — immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).

    Article  CAS  Google Scholar 

  12. Bird, J. J. et al. Helper T-cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).

    Article  CAS  Google Scholar 

  13. Langenkamp, A., Messi, M., Lanzavecchia, A. & Sallusto, F. Kinetics of dendritic-cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nature Immunol. 1, 311–316 (2000).

    Article  CAS  Google Scholar 

  14. Iezzi, G., Scheidegger, D. & Lanzavecchia, A. Migration and function of antigen-primed nonpolarized T lymphocytes in vivo. J. Exp. Med. 193, 987–993 (2001).

    Article  CAS  Google Scholar 

  15. Langenkamp, A. et al. T-cell priming by dendritic cells: thresholds for proliferation, differentiation and death and intraclonal functional diversification. Eur. J. Immunol. 32, 2046–2054 (2002).

    Article  CAS  Google Scholar 

  16. Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  Google Scholar 

  17. Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1-lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  18. Iezzi, G., Scotet, E., Scheidegger, D. & Lanzavecchia, A. The interplay between the duration of TCR and cytokine signalling determines T-cell polarization. Eur. J. Immunol. 29, 4092–4101 (1999).

    Article  CAS  Google Scholar 

  19. Richter, A., Lohning, M. & Radbruch, A. Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell-cycle progression. J. Exp. Med. 190, 1439–1450 (1999).

    Article  CAS  Google Scholar 

  20. Szabo, S. J. et al. Distinct effects of T-bet in TH1-lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).

    Article  CAS  Google Scholar 

  21. Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).

    Article  CAS  Google Scholar 

  22. Tzachanis, D. et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature Immunol. 2, 1174–1182 (2001).

    Article  CAS  Google Scholar 

  23. Chen, W., Jin, W. & Wahl, S. M. Engagement of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor-β (TGF-β) production by murine CD4+ T cells. J. Exp. Med. 188, 1849–1857 (1998).

    Article  CAS  Google Scholar 

  24. Mercado, R. et al. Early programming of T-cell populations responding to bacterial infection. J. Immunol. 165, 6833–6839 (2000).

    Article  CAS  Google Scholar 

  25. Kaech, S. M. & Ahmed, R. Memory CD8+ T-cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunol. 2, 415–422 (2001).

    Article  CAS  Google Scholar 

  26. van Stipdonk, M. J., Lemmens, E. E. & Schoenberger, S. P. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nature Immunol. 2, 423–429 (2001).

    Article  CAS  Google Scholar 

  27. Bevan, M. J. & Fink, P. J. The CD8 response on autopilot. Nature Immunol. 2, 381–382 (2001).

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. 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 

  30. 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 

  31. Wang, X. & Mosmann, T. In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-γ, and can subsequently differentiate into IL-4- or IFN-γ-secreting cells. J. Exp. Med. 194, 1069–1080 (2001).

    Article  CAS  Google Scholar 

  32. Roman, E. et al. CD4 effector T-cell subsets in the response to influenza: heterogeneity, migration and function. J. Exp. Med. 196, 957–968 (2002).

    Article  CAS  Google Scholar 

  33. Hernandez, J., Aung, S., Marquardt, K. & Sherman, L. A. Uncoupling of proliferative potential and gain of effector function by CD8+ T cells responding to self-antigens. J. Exp. Med. 196, 323–333 (2002).

    Article  CAS  Google Scholar 

  34. Badovinac, V. P., Porter, B. B. & Harty, J. T. Programmed contraction of CD8+ T cells after infection. Nature Immunol. 3, 619–626 (2002).

    Article  CAS  Google Scholar 

  35. Plas, D. R., Rathmell, J. C. & Thompson, C. B. Homeostatic control of lymphocyte survival: potential origins and implications. Nature Immunol. 3, 515–521 (2002).

    Article  CAS  Google Scholar 

  36. Sprent, J. & Surh, C. D. Generation and maintenance of memory T cells. Curr. Opin. Immunol. 13, 248–254 (2001).

    Article  CAS  Google Scholar 

  37. Grayson, J. M., Zajac, A. J., Altman, J. D. & Ahmed, R. Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).

    Article  CAS  Google Scholar 

  38. Boise, L. H. et al. CD28 costimulation can promote T-cell survival by enhancing the expression of Bcl-XL . Immunity 3, 87–98 (1995).

    Article  CAS  Google Scholar 

  39. Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).

    Article  CAS  Google Scholar 

  40. Scheinecker, C., McHugh, R., Shevach, E. M. & Germain, R. N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1079–1090 (2002).

    Article  CAS  Google Scholar 

  41. Liu, K. et al. Immune tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196, 1091–1097 (2002).

    Article  CAS  Google Scholar 

  42. Shevach, E. M. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002).

    Article  CAS  Google Scholar 

  43. Zheng, L. et al. Induction of apoptosis in mature T cells by tumour-necrosis factor. Nature 377, 348–351 (1995).

    Article  CAS  Google Scholar 

  44. Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).

    Article  CAS  Google Scholar 

  45. Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nature Rev. Immunol. 2, 251–262 (2002).

    Article  CAS  Google Scholar 

  46. 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 

  47. Goldrath, A. W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).

    Article  CAS  Google Scholar 

  48. Tan, J. T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).

    Article  CAS  Google Scholar 

  49. Kieper, W. C. et al. Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells. J. Exp. Med. 195, 1533–1539 (2002).

    Article  CAS  Google Scholar 

  50. Becker, T. C. et al. Interleukin-15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195, 1541–1548 (2002).

    Article  CAS  Google Scholar 

  51. Breitfeld, D. et al. Follicular B-helper T cells express CXC-chemokine receptor 5, localize to B-cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).

    Article  CAS  Google Scholar 

  52. Schaerli, P. et al. CXC-chemokine receptor 5 expression defines follicular homing T cells with B-cell helper function. J. Exp. Med. 192, 1553–1562 (2000).

    Article  CAS  Google Scholar 

  53. Messi, M. et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nature Immunol. (in the press) (2002).

  54. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  Google Scholar 

  55. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  57. Harris, N. L., Watt, V., Ronchese, F. & Le Gros, G. Differential T-cell function and fate in lymph node and nonlymphoid tissues. J. Exp. Med. 195, 317–326 (2002).

    Article  CAS  Google Scholar 

  58. Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).

    Article  CAS  Google Scholar 

  59. Wu, C. Y. et al. Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo. Nature Immunol. 3, 852–858 (2002).

    Article  CAS  Google Scholar 

  60. Doyle, A. G., Buttigieg, K., Groves, P., Johnson, B. J. & Kelso, A. The activated type 1-polarized CD8+ T-cell population isolated from an effector site contains cells with flexible cytokine profiles. J. Exp. Med. 190, 1081–1092 (1999).

    Article  CAS  Google Scholar 

  61. Liu, Y. J. & Banchereau, J. Regulation of B-cell commitment to plasma cells or to memory B cells. Semin. Immunol. 9, 235–240 (1997).

    Article  CAS  Google Scholar 

  62. Calame, K. L. Plasma cells: finding new light at the end of B-cell development. Nature Immunol. 2, 1103–1108 (2001).

    Article  CAS  Google Scholar 

  63. Fearon, D. T., Manders, P. & Wagner, S. D. Arrested differentiation, the self-renewing memory lymphocyte and vaccination. Science 293, 248–250 (2001).

    Article  CAS  Google Scholar 

  64. Kuo, C. T., Veselits, M. L. & Leiden, J. M. LKLF: a transcriptional regulator of single-positive T-cell quiescence and survival. Science 277, 1986–1990 (1997).

    Article  CAS  Google Scholar 

  65. Mittrucker, H. W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B- and T-lymphocyte function. Science 275, 540–543 (1997).

    Article  CAS  Google Scholar 

  66. Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    Article  CAS  Google Scholar 

  67. Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363 –372(1998).

    Article  CAS  Google Scholar 

  68. Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science (in the press) (2002).

Download references

Acknowledgements

We thank Klaus Karjalainen for critical reading of this manuscript and suggestions. A. L. is supported by the Helmut Horten Foundation and by a grant from the Swiss National Science Foundation. F.S. is supported by a grant from The European Community.

Author information

Authors and Affiliations

  1. the Institute for Research in Biomedicine, Via Vela 6, Bellinzona, CH-6500, Switzerland

    Antonio Lanzavecchia & Federica Sallusto

Authors
  1. Antonio Lanzavecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica Sallusto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Antonio Lanzavecchia or Federica Sallusto.

Related links

Related links

DATABASES

LocusLink

BCL-2

BCL-6

BCL-XL

BLIMP1

CCR7

CD40

CD40L

CTLA4

GATA3

IFN-γ

IL-2

IL-4

IL-6

IL-7

IL-7R

IL-10

IL-12

IL-15

IL-15R

IRF4

LKLF

L-selectin

PAX5

T-bet

TGF-β

TOB

FURTHER INFORMATION

Institute for Research in Biomedicine, Bellinzona

Glossary

CENTRAL-MEMORY CELLS

Memory T and B cells that home to secondary lymphoid organs. These cells are heterogeneous and do not have the full range of functions that are characteristic of effector T cells or plasma cells. They are responsible for secondary or chronic responses to antigen and might be involved in long-term maintenance of effector-memory cells.

CROSS-PRESENTATION

The presentation of exogenous antigen by MHC class I molecules.

DIFFERENTIATION

Refers to changes in the expression of genes that control the cell cycle, fitness, homing, effector function and survival. These transcriptional programmes can be regulated coordinately — for example, homing and effector function.

EFFECTOR-MEMORY CELLS

Memory T cells that home to peripheral tissues and plasma cells that home to the bone marrow and secrete antibodies. They are responsible for immediate protection against antigen challenge.

EPIGENETIC

Refers to the heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin or covalent modifications of DNA and histones.

INTERMEDIATES

Clonally expanded T cells that have been arrested at an intermediate stage of differentiation. Depending on the strength of signal that is received, these cells express different levels of fitness, effector function and migratory capacity.

SIGNAL STRENGTH

Refers to the overall amount of signal transduced through the T-cell receptor. This is determined by the concentration of antigen, extent of signal amplification by co-stimulatory molecules and duration of the antigen-presenting-cell–T-cell interaction. These parameters can vary widely and in a stochastic fashion.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lanzavecchia, A., Sallusto, F. Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol 2, 982–987 (2002). https://doi.org/10.1038/nri959

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri959

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing