Cytokine-driven proliferation and differentiation of human naïve, 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+ naïve 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 naïve T cells did not respond at all. Dendritic cell (DC)-derived cytokines allowed naïve 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-15Rss and the common gamma chain (gamma(c)). 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 T(EM) 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) from a pool of T(CM) cells.
Geginat
J
J
Institute for research in biomedicine, Via Vincenzo Vela 6, 6500, Bellinzona, Suisse. jens.geginat@irb.unisi.ch <jens.geginat@irb.unisi.ch>
Sallusto
F
F
Lanzavecchia
A
A
D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice
D000941:Antigens; D016207:Cytokines