Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human V gamma 9V delta 2 naive, memory and effector T cell subsets

We have compared four human subsets of V gamma 9V delta 2 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 V gamma 9V delta 2 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.