Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

We have compared four human subsets of Vγ9Vδ2 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 Vγ9Vδ2 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.