Cytokine-driven proliferation and differentiation of human naive, central memory and effector memory CD4+ T cells

Memory T lymphocytes divide in vivo in the absence of antigen maintaining a pool of central memory (T-CM) and effector memory cells (T-EM) with distinct effector function and homing capacity. We compared human CD4(+) naive T, T-CM and T-EM cells for their capacity to proliferate in response to cytokines. which have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency T-EM, while T-CM were less responsive and naive T cells did not respond at all. Dendritic cell (DC)-derived cytokines allowed naive T cells to respond selectively to IL-4 and potently boosted the response of T-CM to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rbeta and the common gamma chain (gammac). The ERK and the p38 MAP kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures T-CM proliferated and some of the proliferating cells acquired effector function and non-lymphoid tissue homing capacity. Ex vivo BrdU incorporation experiments showed that both T-CM and Term, proliferated under steady state conditions in vivo. Altogether these results provide a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4(+) memory T cells and for a sustained antigen-independent generation of T-EM froth a pool of T-CM cells. (C) 2002 Editions scientifiques et medicates Elsevier SAS. All rights reserved.