The Journal of Experimental Medicine
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Published 10 December 2001. doi:10.1084/jem.194.12.1711
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© Rockefeller University Press, 0022-1007/2001/12/1711/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 12, December 17, 2001 1711-1720

Original Article

Cytokine-driven Proliferation and Differentiation of Human Naive, Central Memory, and Effector Memory CD4+ T Cells

Jens Geginat, Federica Sallusto and Antonio Lanzavecchia

Institute for Research in Biomedicine, Bellinzona 6500, Switzerland

Address correspondence to J. Geginat, Institute for Research in Biomedicine, Via Vela 6, Bellinzona 6500, Switzerland. Phone: 41-91-8200-342; Fax: 41-91-8200-302; E-mail: jens.geginat{at}irb.unisi.ch

Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (TCM) and effector memory T cells (TEM) with distinct effector function and homing capacity. We compared human CD4+ naive T, TCM, and TEM 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 TEM, while TCM 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 TCM to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rß 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 TCM differentiated to TEM-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of TEM 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.

Key Words: human CD4+ T cell subsets • memory maintenance • cytokines • differentiation • proliferation


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