Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection.
After acute infection Epstein-Barr virus (EBV)-specific memory CD8+ T cells exit cell cycle, and a proportion of these antigen-experienced cells re-express CD45RA (CD45 which predominantly express exon A). However, the signals involved are not known. We investigated the roles of interleukin 15 (IL-15) and interferon-alpha/beta (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8+ T-cell memory. We show that IFN-I (but not IL-15) allows activated EBV-specific CD8+ T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I) induced "homeostatic" proliferation and CD45RA re-expression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA re-expression in activated EBV-specific CD8+ T cells. After T-cell receptor (TCR) activation freshly isolated CD45RA+ antigen-experienced CD8+ T cells show poor proliferative activity but are highly cytotoxic and secrete IFN-gamma efficiently. This suggests functional reprogramming toward effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8+ T cells that re-express CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.
Dunne
Pádraic J
PJ
Division of Infection and Immunity, 46 Cleveland St, University College London, W1T 4JF United Kingdom.
Belaramani
Lavina
L
Fletcher
Jean M
JM
Fernandez de Mattos
Silvia
S
Lawrenz
Maria
M
Soares
Maria Vieira D
MV
Rustin
Malcolm H A
MH
Lam
Eric W-F
EW
Salmon
Mike
M
Akbar
Arne N
AN
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D002453:Cell Cycle; D003602:Cytotoxicity, Immunologic; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology
D007370:Interferon Type I; D019409:Interleukin-15; D011994:Recombinant Proteins; D017493:Leukocyte Common Antigens