Alkylphosphate and tumor cell recognition by circulating Vgamma2Vdelta2 T cells

Abstract

The antigen receptor on T cells is a heterodimer consisting of either alpha and beta (alphabeta) or gamma and delta (gammadelta) chains. Mechanisms that control repertoire selection in the alphabeta subset are well known, involving positive and negative selection in the thymus and subsequent regulation by peripheral tolerance. Mechanisms controlling gammadelta T cell repertoire selection are poorly understood, partly because antigen recognition by this receptor is MHC-unrestricted and partly due to our inability to define receptor-binding antigens for the major Vgamma2Vdelta2 subset. Clues to antigen recognition come from the pattern of repertoire selection, including the dominant appearance of the Vgamma2Vdelta2 T cell receptor (TCR) and even more specifically, a strong bias for Vgamma2 chains encoding the Jgamma1.2 segment. In healthy human adults, the majority of circulating gammadelta T cells express the Vgamma2-Jgamma1.2Vdelta2 TCR and respond to stimulation with a variety of phosphoantigens as well as some tumor cells. Analysis of the Vgamma2 chain repertoire during active responses to tumors or phosphoantigens demonstrates a remarkable similarity among individual T cell clones that proliferate in response to either stimulus. Vgamma2 chains responding only to phosphoantigens or tumor cells were possible but infrequent, suggesting that the Vgamma2 repertoire evolved to recognize ligands present on tumor cells or elicited following phosphoantigen treatment. Surprisingly, the repertoire of Vgamma2-Jgamma1.2Vdelta2 T cells that exists in healthy adults is stable over intervals as long as seven years, showing that a population of T cells reactive to self molecules including phosphoantigens, resists negative selection mechanisms of the type controlling MHC-restricted alphabeta T cells and evades peripheral tolerance. Repertoire stability is altered abruptly in the face of HIV infection, wherein we noted a dramatic and specific depletion of the Vgamma2-Jgamma1.2 subset. The loss of Vgamma2-Jgamma1.2Vdelta2 T cells during HIV infection is correlated with an increased susceptibility to tumors and opportunistic pathogens that are characteristic of advanced HIV disease, when the gammadelta T cell loss is most extreme. These studies describe an unconventional T cell subset with an acquired TCR repertoire generated in the absence of MHC restriction that has the capacity for responses to a broad array of pathogens and tumors.