Skip to main content
SpringerLink
Log in

Stability of a diverse immunological memory is determined by T cell population dynamics

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

The correlation between properties of the T cell memory pool and the two regulatory mechanisms of cell death (apoptosis) and memory entry (differentiation) is investigated mathematically. Apoptosis of T cells occurs at the end of an immune response, removing unwanted activated T cells. T cells escaping apoptosis enter the memory pool composed of T cells specific for previously encountered antigens. We find that the relative efficiencies of these two pathways determine the clonal distribution and the long-term stability of the memory pool by regulating the number of new entries. The main result presented in this paper is that immunological memory of previously encountered pathogens cannot be erased by either severe or repeat infections with a particular pathogen (the diversity of the memory pool is ensured) only if apoptosis and/or memory differentiation are regulated by population dependent processes. Furthermore, vaccination properties are improved significantly by population dependent mechanisms and our mathematical analysis reveals that the T cell population must communicate with other parts of the immune system to ensure optimal performance of immunological memory.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbas, A. K. (1996). Die and let live: eliminating dangerous lymphocytes. Cell 84, 655–657.

    Article  Google Scholar 

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

    Google Scholar 

  • Akbar, A. N., N. J. Brothwick, G. R. Wickremasinghe, P. Panayiotidis, D. Pilling, M. Bofill, S. Krajewski, J. C. Reed and M. Salmon (1996). Interleukin-2 receptor common γ-chain signalling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-x L ) but not pro-apoptotic (bax, bcl-x S ) gene expression. Eur. J. Immunol. 26, 294–299.

    Google Scholar 

  • Akbar, A. N. and M. Salmon (1997). Cellular environments and apoptosis: tissue microenvironments control activated T cell death. Immunol. Today 18, 72–76.

    Article  Google Scholar 

  • Antia, R., S. S. Pilyugin and R. Ahmed (1998). Models of immune memory: on the role of cross-reactive stimulation, competition, and homeostasis in maintaining immune memory. Proc. Natl. Acad. Sci. USA 95, 14926–14931.

    Google Scholar 

  • Bell, E. B., S. M. Sparshott and C. Bunce (1998). CD4+ T cell memory, CD45R subsets and the persistence of antigen a unifying concept. Immunol. Today 19, 60–64.

    Article  Google Scholar 

  • Bradley, L. M. and S. R. Watson (1996). Lymphocyte migration into tissue: the paradigm derived from CD4 subsets. Curr. Opin. Immunol. 8, 312–320.

    Article  Google Scholar 

  • Broome, H. E., C. M. Dargan, E. F. Bessent, S. Krajewski and J. C. Reed (1995). Apoptosis and Bcl-2 expression in cultured murine splenic T cells. Immunology 84, 375–382.

    Google Scholar 

  • DeBoer, R. J. and A. S. Perelson (1994). T cell repertoires and competitive exclusion. J. Theor. Biol. 169, 375–390.

    Article  Google Scholar 

  • Duke, R. C. and J. J. Cohen (1986). IL-2 addiction—withdrawal of growth-factor activates a suicide program in dependent T cells. Lymphokine Res. 5, 289–299.

    Google Scholar 

  • Dutton, R. W., L. M. Bradley and S. L. Swain (1998). T cell memory. Annu. Rev. Immunol. 16, 201–223.

    Article  Google Scholar 

  • Freitas, A. A. and B. Rocha (2000). Population biology of lymphocytes: the flight for survival. Annu. Rev. Immunol 18, 83–111.

    Article  Google Scholar 

  • Gradstein, I. S. and I. M. Ryzhik Table of Integrals, Series and Products, 5th edn, San Diego: Academic Press.

  • Gray, D. and P. Matzinger (1991). T cell memory is short-lived in the absence of antigen. J. Exp. Med. 174, 969–974.

    Article  Google Scholar 

  • Greene, W. C. and W. J. Leonard (1986). The human interleukin-2 receptor. Annu. Rev. Immunol. 4, 69–95.

    Article  Google Scholar 

  • Hémar, A., A. Subtil, M. Lieb, E. Morelon, R. Hellio and A. Dautry-Varsat (1995). Endocytosis of interleukin-2 receptors in human T-lymphocytes—distinct intracellular localisation and fate of the receptor alpha-chain, beta-chain, and gamma-chain. J. Cell Biol. 129, 55–64.

    Article  Google Scholar 

  • Jacob, J. and D. Baltimore (1999). Modelling T cell memory by genetic marking of memory Tcells in vivo. Nature 399, 593–597.

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Lenardo, M., C. F. Ka-Ming, F. Hornung, H. McFarland, R. Siegel, J. Wang and L. Zheng (1999). Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253.

    Article  Google Scholar 

  • Lynch, D. H., F. Ramsdell and M. R. Alderson (1995). Fas and FasL in the homeostatic regulation of immune responses. Immunol. Today 16, 569–574.

    Article  Google Scholar 

  • Mackay, C. R. (1993). Homing of naïve, memory and effector lymphocytes. Curr. Opin. Immunol. 5, 423–427.

    Article  Google Scholar 

  • Maple V release 5.1.

  • McHeyzer Williams, M. G. and M. M. Davis (1995). Antigen-specific development of primary and memory T cells in vivo. Science 268, 106–111.

    Google Scholar 

  • McLean, A. R. (1994). Modelling T cell memory. J. Theor. Biol. 170, 63–74.

    Article  Google Scholar 

  • Michie, C. A., A. McLean, C. Alcock and P. C. L. Beverley (1992). Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265.

    Article  Google Scholar 

  • Miyawaki, T., T. Uehara, R. Nibu, T. Tsuji, A. Yachie, S. Yonehara and N. Taniguchi (1992). Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J. Immunol. 149, 3753–3758.

    Google Scholar 

  • Murali-Krishna, K. et al. (1998). Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immmunity 8, 177–187.

    Article  Google Scholar 

  • Murray, J. D. (1989). Mathematical Biology, Berlin: Springer.

    Google Scholar 

  • Orteu, C. H., L. W. Poulter, M. H. A. Rustin, C. A. Sabin, M. Salmon and A. N. Akbar (1998). The role of apoptosis in the resolution of T-cell-mediated cutaneous inflammation. J. Immunol. 161, 1619–1629.

    Google Scholar 

  • Pilling, D., A. N. Akbar, J. Girdlestone, C. H. Orteu, N. J. Borthwick, N. Amft, D. Schell-Toellner, C. D. Buckley and M. Salmon (1999). Interferon-β mediates stromal cell rescue of T cells from apoptosis. Eur. J. Immunol. 29, 1041–1050.

    Article  Google Scholar 

  • Schell-Toellner, D., D. Pilling, A. N. Akbar, D. Hardie, G. Lombardie, M. Salmon and J. M. Lord (1999). Inhibition of T cell apoptosis by IFN-β rapidly reverses nuclear translocation of protein kinases. Eur. J. Immunol. 29, 2603–2612.

    Article  Google Scholar 

  • Selin, L. K., K. Vergilis, R. M. Welsh and R. S. Nahill (1996). Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J. Exp. Med. 183, 2489–2499.

    Article  Google Scholar 

  • Selin, L. K. and R. M. Welsh (1997). Cytolytikally active memory CTL present in lymphocytic choriomeningitis virus-immune mice after clearance of virus infection. J. Immunol. 158, 5366–5373.

    Google Scholar 

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

    Article  Google Scholar 

  • Takeda, S., H. R. Rodewald, H. Arakawa, H. Bluethmann and T. Shimizu (1996). MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity 5, 217–228.

    Article  Google Scholar 

  • Tanchot, C., F. A. Lemonnier, B. Perarnau, A. A. Freitas and B. Rocha (1997). Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2075–2062.

    Article  Google Scholar 

  • Thomson, A. (1998). Cytokine Handbook, San Diego: Academic Press.

    Google Scholar 

  • Tough, D. F., S. Siquan, Z. Xiaohong and J. Sprent (1999). Stimulation of naive and memory T cells by cytokines. Immunol. Rev. 170, 39–47.

    Article  Google Scholar 

  • Varga, S. M. and R. M. Welsh (1998). Stability of virus-specific CD4+ T cell frequencies from acute infection into long term memory. J. Immunol. 161, 367–374.

    Google Scholar 

  • Waldmann, T. A. (1989). The multi-subunit interleukin-2 receptor. Annu. Rev. Biochem. 58, 875–911.

    Article  Google Scholar 

  • Webb, L. M. C., B. M. J. Focwell and M. Feldmann (1999). Putative role for interleukin-7 in the maintenance of the reciruclating naiveCD4+ T cell pool. Immunology 98, 400–405.

    Article  Google Scholar 

  • Zheng, L., C. L. Trageser, D. M. Willerford and M. J. Lenardo (1998). T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. J. Immunol. 160, 763–769.

    Google Scholar 

  • Zimmermann, C., A. Prévost-Blondel, C. Blaser and H. Pircher (1999). Kinetics of the reponse of naive and memory CD8 T cells to antigen: similarities and differences. Eur. J. Immunol. 29, 284–290.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mathematics Institute, University of Warwick, Coventry, CV4 7AL, UK

    C. Utzny & N. J. Burroughs

Authors
  1. C. Utzny
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. J. Burroughs
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Utzny, C., Burroughs, N.J. Stability of a diverse immunological memory is determined by T cell population dynamics. Bull. Math. Biol. 63, 685–713 (2001). https://doi.org/10.1006/bulm.2001.0242

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1006/bulm.2001.0242

Keywords

Search

Navigation