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-15Rbeta and the common gamma chain (gamma(c)). 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.
Geginat
J
J
Institute for Research in Biomedicine, Bellinzona 6500, Switzerland. jens.geginat@irb.unisi.ch
Sallusto
F
F
Lanzavecchia
A
A
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007156:Immunologic Memory; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
D016207:Cytokines