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

Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (T-CM) and effector memory T 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, that 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 failed to respond. Dendritic cells (DCs) and DC-derived cytokines allowed naive T cells to proliferate selectively in response 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-15R beta and the common gamma chain (gammac). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCP, and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating Tcm differentiated to T-EM-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCP5. The sustained antigen-independent generation of T-EM from a pool of Tcm cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4(+) memory T cells.