Human V 2V 2 T cells contain cytoplasmic RANTES

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Abstract
The adult human Vγ2Vδ2 T cell repertoire is a product of chronic selection in the periphery. Endogenous antigens drive the expansion of cells expressing the Vγ2Vδ2 TCR. Thus, we would expect the majority of circulating Vγ2Vδ2 T cells to be antigen experienced and to have memory phenotype, in contrast to the alpha/beta TCR+ subsets that include a substantial fraction of naive cells. We sought to characterize functional aspects of Vγ2Vδ2 T cells that might show whether circulating cells are memory or naive. For these studies, we focus on the expression of the CC chemokine regulated upon activation normal T cell expressed and secreted (RANTES). In naive αβ T cells, an initial stimulus triggers the onset of RANTES transcription followed later by protein expression. In memory CD8+ αβ T cells, RANTES mRNA is already present in unstimulated cells and protein expression is triggered immediately by TCR signaling; some cells may also contain RANTES protein in cytoplasmic stores. We show here that the vast majority of circulating human T cells contain RANTES protein in cytoplasmic stores and the chemokine is secreted rapidly after TCR signaling. Primary Vγ2Vδ2 T cell lines obtained after in vitro stimulation with phosphoantigens behaved similarly to circulating Vγ2Vδ2 T cells and contained both RANTES mRNA and protein, but only very low levels of mRNA or protein for macrophage inflammatory protein (MIP)-1α or MIP-1β. The presence of stored RANTES shows that circulating Vγ2Vδ2 T cells are mostly memory phenotype and capable of rapid chemokine responses to phosphoantigen stimulation. Considering that one of 40 circulating CD3+ lymphocytes is Vγ2Vδ2+, they comprise the largest circulating memory population against a single antigen, and phosphoantigen stimulation will trigger a rapid activation with immediate release of RANTES.