TGF-β enhances the cytotoxic activity of Vδ2 T cells

TGF-beta is a pleiotropic cytokine with multiple roles in immunity. Apart from its suppressive activity, TGF-beta is a driving cytokine in the differentiation of induced regulatory T cells (iTreg) but also in the polarization of interleukin-9 (IL-9) producing T helper 9 (Th9) T cells. Human V delta 2 expressing gamma delta T cells exert potent cytotoxicity towards a variety of solid tumor and leukemia/lymphoma target cells and thus are in the focus of current strategies to develop cell-based immunotherapies. Here we report that TGF-beta unexpectedly augments the cytotoxic effector activity of short-term expanded V delta 2 T cells when purified gamma delta T cells are activated with specific pyrophosphate antigens and IL-2 or IL-15 in the presence of TGF-beta. TGF-beta up-regulates the expression of CD54, CD103, interferon-gamma , IL-9 and granzyme B in gamma delta T cells while CD56 and CD11a/CD18 are down-regulated. Moreover, we show that CD103 (alpha E/beta 7 integrin) is recruited to the immunological synapse in gamma delta T cells. Increased cytotoxic activity of TGF-beta-exposed gamma delta T cells is reduced by anti-CD103 and further diminished upon additional anti-CD11a antibody treatment, pointing to a role of cellular adhesion in the enhanced cytolytic activity. Furthermore, magnetically sorted CD103-positive V delta 2 T cells exhibit superior cytolytic activity. In view of the importance of CD103 for tissue homing of lymphocytes, our results suggest that adoptive transfer of CD103-expressing V delta 2 T cells might favor their homing to solid tumors.