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-15Rβ and the common γ chain (γc). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating T_CM differentiated to T_EM-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of T_EM from a pool of T_CM cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4⁺ memory T cells.