| Recently, a new helper T cell population, Th17 cells, has been identified. Th17 cells are characterized by the secretion of IL-17, IL-17F, IL-22 and IL-21, and the expression of transcription factors RORgammat, RORalpha, STAT3 and IRF4. Th17 cells have been implicated in allograft rejection of solid organs and many autoimmune diseases. However, no studies have addressed the functional role of Th17 cells in development of acute graft-versus-host disease (GVHD). We detected alloreactive donor Th17 cells in lymphoid organs from allogeneic and syngeneic mouse bone marrow transplant (BMT) recipients. Upon transfer of murine IL-17 deficient CD4+ T cells, GVHD development was significantly delayed. We observed that recipients of IL-17-/-CD4+ T cells have significantly fewer donor Th1 cells and IFN-gamma-secreting myeloid cells compared to recipients of WT CD4+ B6 T cells. In addition, lymphoid cells from recipients of IL-17-/-CD4+ T cells produce less IL-4 and IL-6 compared to recipients of WT CD4+ B6 T cells. To further investigate the role of Th17-related cytokines in GVHD, we utilized IL-21R-/- T cells as donor T cells in two different allo-BMT models and we found that IL-21 signaling on donor T cells exacerbates GVHD. Furthermore, our studies suggest that the perturbation of IL-21 signaling on donor T cells results in expansion of regulatory T cells, increased production of IL-10, and decreased production of proinflammatory cytokine, such as TNF-alpha and IL-4. These results suggest that TH17 cells contribute to GVHD by amplifying the proinflammatory cytokine milieu, and the targeting of TH17 cells after allo-BMT may provide a new approach for GVHD treatment. |
