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

We previously demonstrated that gamma delta T cells played an important role in tumor immune surveillance by providing an early source of IFN-gamma. The precise role of different subsets of gamma delta T cells in the antitumor immune response, however, is unknown. V gamma 1 and V gamma 4 gamma delta T cells are the principal subsets of peripheral lymphoid gamma delta T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCR delta(-/-) mice with V gamma 4, but not V gamma 1, gamma delta T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44(high)) portion of V gamma 4 gamma delta T cells. We further determined that IFN-gamma and perforin are critical elements in the V gamma 4-mediated antitumor immune response. Indeed, CD44(high) V gamma 4 gamma delta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) V gamma 1 gamma delta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated V gamma 4 gamma delta T cells. Consistently, transfection of dominant-negative Eomes in V gamma 4 gamma delta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gamma delta T cells. Our results thus reveal distinct functions of V gamma 4 and V gamma 1 gamma delta T cells in antitumor immune response, and identify a protective role of activated V gamma 4 gamma delta T cells, with possible implications for tumor immune therapy. The Journal of Immunology, 2010, 185: 126-133.