Vγ2 γδ T Cells in the Presence of Anti-CD40L Control Surgical Inflammation and Promote Skin Allograft Survival.

γδ T cells represent a small fraction of total T cells in the body and do not use classical polymorphic major histocompatibility complex‒loaded peptides for mounting an immune response. The importance of the effector and regulatory function of γδ T cells in infections, autoimmunity, and tumor models are well characterized. In this study, we investigated the mechanistic role of γδ T cells in costimulatory blockade‒induced transplantation tolerance. We used donor-specific transfusion and anti-CD40L treatment in C57BL/6 mice to induce tolerance to BALB/c skin allografts. We show that depletion of γδ T cells, specifically Vγ2 γδ T cells, led to the acute rejection of skin allografts despite tolerogen treatment. Tolerogen treatment promoted CD39Vγ2 γδ T cells and suppressed IFN-γ‒producing Vγ2 γδ T cells in the spleen and allografts. Vγ2 γδ T cells isolated from tolerized mice suppress T helper type 1 cell differentiation. Adoptive transfer of these regulatory Vγ2 γδ T cells prolonged the survival of allografts in an untreated recipient and Tcrδ mice. Together, our data show that the Vγ2 subset promotes costimulatory blockade‒induced survival of skin allografts and that tolerogenic Vγ2 T cells can be used as an adoptive cellular therapy to promote the survival of allografts.