We have compared four human subsets of Vgamma9Vdelta2 T cells, naive (T(naive), CD45RA(+)CD27(+)), central memory (T(CM), CD45RA(-)CD27(+)), effector memory (T(EM), CD45RA(-)CD27(-)) and terminally differentiated (T(EMRA), CD45RA(+)CD27(-)), for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and IL-15R expression were low in T(naive) cells and progressively increased from T(CM) to T(EM) and T(EMRA) cells. In contrast, the capacity to expand in response to antigen or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas antigen-stimulated cells acquired a T(CM) or T(EM) phenotype, IL-15-stimulated cells maintained their phenotype, with the exception of T(CM) cells, which expressed CD27 and CD45RA in various combinations. These results, together with ex vivo bromodeoxyuridine incorporation experiments, show that human Vgamma9Vdelta2 memory T cells have different proliferation and differentiation potentials in vitro and in vivo and that T(EMRA) cells are generated from the T(CM) subset upon homeostatic proliferation in the absence of antigen.