Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells


The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naïve CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naïve CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Varying the antigen dose affects the magnitude of the CD8+ T cell response and the recruitment of naïve CD8+ T cells, but all recruited cells divide extensively.
Figure 2: CD8+ T cells become committed to differentiate fully into effector CTLs after initial activation.
Figure 3: Activated CD8+ T cells continue to divide in the absence of antigenic stimulation in vitro.
Figure 4: Repeated exposure to antigen is not necessary for activated CD8+ T cells to divide several times and differentiate into effector CTLs in vivo.
Figure 5: IL-2 is important for activated CD8+ T cells proliferating in the ab-sence of continuous antigenic stimulation.
Figure 6: Activated CD8+ T cells are programmed to differentiate into long-lived, functional memory CD8+ T cells.
Figure 7: Memory CD8+ T cells generated in antigen-limiting conditions can confer protective immunity.
Figure 8: Models for proliferation and differentiation of naïve CD8+ T cells.


  1. 1

    Ahmed, R. & Biron, C. A. in Fundamental Immunology (ed. Paul, W. E.) 1295–1333 (Lippincott-Raven Publishers, Philadelphia, 1999).

  2. 2

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

  3. 3

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

  4. 4

    Agarwal, S. & Rao, A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9, 765–775 (1998).

  5. 5

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

  6. 6

    Oehen, S. & Brduscha-Riem, K. Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J. Immunol. 161, 5338–5346 (1998).

  7. 7

    Bachmann, M. F., Barner, M., Viola, A. & Kopf, M. Distinct kinetics of cytokine production and cytolysis in effector and memory T cells after viral infection. Eur. J. Immunol. 29, 291–299 (1999).

  8. 8

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

  9. 9

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

  10. 10

    Veiga-Fernandes, H., Walter, U., Bourgeois, C., McLean, A. & Rocha, B. Response of naive and memory CD8+ T cells to antigen stimulation in vivo. Nature Immunol. 1, 47–53 (2000).

  11. 11

    Busch, D. H., Pilip, I. M., Vijh, S. & Pamer, E. G. Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 8, 353–362 (1998).

  12. 12

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

  13. 13

    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).

  14. 14

    Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

  15. 15

    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).

  16. 16

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

  17. 17

    Weintraub, H., Flint, S. J., Leffak, I. M., Groudine, M. & Grainger, R. M. The generation and propagation of variegated chromosome structures. Cold Spring Harb. Symp. Quant. Biol. 42, 401–407 (1978).

  18. 18

    Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370, 463–467 (1994).

  19. 19

    Wills, M. al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T- cell receptor usage of pp65-specific CTL. J. Virol. 70, 7569–7579 (1996).

  20. 20

    Callan, M. al. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nature Med. 2, 906–911 (1996).

  21. 21

    Sunil-Chandra, N. P., Arno, J., Fazakerley, J. & Nash, A. A. Lymphoproliferative disease in mice infected with murine γ herpesvirus 68. Am. J. Pathol. 145, 818–826 (1994).

  22. 22

    Mullbacher, A. The long-term maintenance of cytotoxic T cell memory does not require persistence of antigen. J. Exp. Med. 179, 317–321 (1994).

  23. 23

    Murata, K. et al. Characterization of in vivo primary and secondary CD8+ T cell responses induced by recombinant influenza and vaccinia viruses. Cell. Immunol. 173, 96–107 (1996).

  24. 24

    Pircher, H., Rohrer, U. H., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351, 482–485 (1991).

  25. 25

    Zimmerman, C., Brduscha-Riem, K., Blaser, C., Zinkernagel, R. M. & Pircher, H. Visualization, characterization, and turnover of CD8+ memory T cells in virus-infected hosts. J. Exp. Med. 183, 1367–1375 (1996).

  26. 26

    Harrington, L. E., Galvan, M., Baum, L. G., Altman, J. D. & Ahmed, R. Differentiating between memory and effector CD8 T cells by altered expression of cell surface O-glycans. J. Exp. Med. 191, 1241–1246 (2000).

  27. 27

    Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

  28. 28

    Matloubian, M., Somasundaram, T., Kolhekar, S. R., Selvakumar, R. & Ahmed, R. Genetic basis of viral persistence: single amino acid change in the viral glycoprotein affects ability of lymphocytic choriomeningitis virus to persist in adult mice. J. Exp. Med. 172, 1043–1048 (1990).

  29. 29

    Ehl, S., Hombach, J., Aichele, P., Hengartner, H. & Zinkernagel, R. M. Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model. J. Exp. Med. 185, 1241–1251 (1997).

  30. 30

    Zarozinski, C. C. & Welsh, R. M. Minimal bystander activation of CD8 T cells during the virus-induced polyclonal T cell response. J. Exp. Med. 185, 1629–1639 (1997).

  31. 31

    Jelley-Gibbs, D. M., Lepak, N. M., Yen, M. & Swain, S. L. Two distinct stages in the transition from naive CD4 T cells to effectors, early antigen-dependent and late cytokine-driven expansion and differentiation. J. Immunol. 165, 5017–5026 (2000).

  32. 32

    Mercado, R. et al. Early Programming of T cell Populations Responding to Bacterial Infection. J. Immunol. 165, 6833–6839 (2000).

  33. 33

    Biron, C. A. Cytokines in the generation of immune responses to, and resolution of, virus infection. Curr. Opin. Immunol. 6, 530–538 (1994).

  34. 34

    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).

  35. 35

    Vijh, S. & Pamer, E. G. Immunodominant and subdominant CTL responses to Listeria monocytogenes infection. J. Immunol. 158, 3366–3371 (1997).

  36. 36

    Shen, H. et al. Compartmentalization of bacterial antigens: differential effects on priming of CD8 T cells and protective immunity. Cell 92, 535–545 (1998).

  37. 37

    Ahmed, R., Salmi, A., Butler, L. D., Chiller, J. M. & Oldstone, M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521–540 (1984).

  38. 38

    Huang, J-F. et al. TCR-mediated internalization of peptide-MHC-complexes acquired by T cells. Science 286, 952–954 (1999).

  39. 39

    Hwang, I. et al. T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells. J. Exp. Med. 191, 1137–1148 (2000).

Download references


We thank R. Antia, B. Evavold, G. Shadel and the Ahmed lab for helpful discussions and critical reading of this manuscript, H. Shen for the recombinant L. monocytogenes strain XFL203 and P. Mahar and K. Madhavi-Krishna for their technical assistance. Supported by National Institutes of Health grant AI30048 (to R. A.) and the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, DRG-1570 (to S.M.K).

Author information



Corresponding author

Correspondence to Rafi Ahmed.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaech, S., Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nat Immunol 2, 415–422 (2001).

Download citation

Further reading