Identification of a novel population of highly cytotoxic c-Met-expressing CD8(+) T lymphocytes.

CD8(+) cytotoxic T lymphocytes (CTLs) are critical mediators of antitumor immunity, and controlling the mechanisms that govern CTL functions could be crucial for enhancing patient outcome. Previously, we reported that hepatocyte growth factor (HGF) limits effective murine CTL responses via antigen-presenting cells. Here, we show that a fraction of murine effector CTLs expresses the HGF receptor c-Met (c-Met(+) CTLs). Phenotypic and functional analysis of c-Met(+) CTLs reveals that they display enhanced cytolytic capacities compared to their c-Met(-) CTL counterparts. Furthermore, HGF directly restrains the cytolytic function of c-Met(+) CTLs in cell-mediated cytotoxicity reactions in vitro and in vivo and abrogates T-cell responses against metastatic melanoma in vivo. Finally, we establish in three murine tumor settings and in human melanoma tissues that c-Met(+) CTLs are a naturally occurring CD8(+) T-cell population. Together, our findings suggest that the HGF/c-Met pathway could be exploited to control CD8(+) T-cell-mediated anti-tumor immunity.