IL-17 contributes to CD4-mediated graft-versus-host disease

Abstract

CD4⁺ interleukin-17 (IL-17)⁺ T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4⁺ donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17^−/− T-cell recipients. However, upon transfer of murine IL-17^−/− CD4⁺ T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4⁺ T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17^−/− CD4⁺ T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-γ–secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-γ, IL-4, and IL-6) in recipients of IL-17^−/− CD4⁺ T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.