Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection

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Abstract
After acute infection Epstein-Barr virus (EBV)-specific memory CD8(+) T cells exit cell cycle, and a proportion of these antigen-experienced cells reexpress 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 reexpression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA reexpression 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 reexpress CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.

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