Naturally Activated Vγ4 γδ T Cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin

Abstract We previously demonstrated that γδ T cells played an important role in tumor immune surveillance by providing an early source of IFN-γ. The precise role of different subsets of γδ T cells in the antitumor immune response, however, is unknown. Vγ1 and Vγ4 γδ T cells are the principal subsets of peripheral lymphoid γδ T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRδ−/− mice with Vγ4, but not Vγ1, γδ T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44high) portion of Vγ4 γδ T cells. We further determined that IFN-γ and perforin are critical elements in the Vγ4-mediated antitumor immune response. Indeed, CD44high Vγ4 γδ T cells produced significantly more IFN-γ and perforin on activation, and showed greater cytolytic activity than did CD44high Vγ1 γδ T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vγ4 γδ T cells. Consistently, transfection of dominant-negative Eomes in Vγ4 γδ T cells diminished the level of IFN-γ secretion, indicating a critical role of Eomes in the effector function of these γδ T cells. Our results thus reveal distinct functions of Vγ4 and Vγ1 γδ T cells in antitumor immune response, and identify a protective role of activated Vγ4 γδ T cells, with possible implications for tumor immune therapy.