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 (Tnaive, CD45RA+CD27+), central memory (TCM, CD45RA–CD27+), effector memory (TEM, CD45RA–CD27–) and terminally differentiated (TEMRA, 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 Tnaive cells and progressively increased from TCM to TEM and TEMRA 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 TCM or TEM phenotype, IL‐15‐stimulated cells maintained their phenotype, with the exception of TCM 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 TEMRA cells are generated from the TCM subset upon homeostatic proliferation in the absence of antigen.