THE ROLE OF NATURAL CYTOTOXICITY RECEPTORS IN THE HOMEOSTASIS AND FUNCTION OF A NEWLY DISCOVERED SUBSET OF HUMAN GAMMA DELTA T CELLS

Natural Cytotoxicity Receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, upon binding to their endogenous ligands, trigger the killing of tumor cell targets. Here we describe a population of Vδ1 + T cells from human peripheral blood that can differentiate in vitro to express the NCRs NKp30, NKp44 and NKp46. Moreover, we show that the expression of NKp30 endows Vδ1 + T cells with the ability to suppress HIV-1 viral replication and lyse hematologic tumor cells in vitro, through the production of CC chemokines and cytolytic granules, respectively. These experiments were also accompanied by the finding that a substantial population of Vδ1 + T cells within the intestinal epithelium expresses all three NCRs, with NKp46 being predominant. While the role for the NCR on expanded populations of γδ T cells from the peripheral blood grants γδ T cells with potent effector functions, we provide evidence that the NCR, and in particular NKp46, is a marker of hyporesponsive γδ T cells in the intestinal epithelium. These data suggest two opposing roles for the NCR on γδ T cells depending on the environment: 1) NCRs which can be induced in vitro are able to impart cytotoxic effector functions on the γδ T cells and 2) NCRs present in physiological conditions in the healthy intestine may function to regulate the γδ T cell. Our findings open exciting new avenues for the understanding of γδ IEL T cell function. Moreover, the induction of NCRs on peripheral γδ T cells in vitro may have direct implications in the development of adoptive cell therapies for the treatment of various diseases including cancer and HIV-1 infection.