γδ T Cells Are Essential Effectors of Type 1 Diabetes in the Nonobese Diabetic Mouse Model

gamma delta T cells, a lineage of innate-like lymphocytes, are distinguished from conventional alpha beta T cells in their Ag recognition, cell activation requirements, and effector functions. gamma delta T cells have been implicated in the pathology of several human autoimmune and inflammatory diseases and their corresponding mouse models, but their specific roles in these diseases have not been elucidated. We report that gamma delta TCR+ cells, including both the CD27(-)CD44(hi) and CD27(+)CD44(lo) subsets, infiltrate islets of prediabetic NOD mice. Moreover, NOD CD27(-)CD44(hi) and CD27(+)CD44(lo) gamma delta T cells were preprogrammed to secrete IL-17, or IFN-gamma upon activation. Adoptive transfer of type 1 diabetes (T1D) to T and B lymphocyte-deficient NOD recipients was greatly potentiated when gamma delta T cells, and specifically the CD27(-) gamma delta T cell subset, were included compared with transfer of alpha beta T cells alone. Ab-mediated blockade of IL-17 prevented T1D transfer in this setting. Moreover, introgression of genetic Tcrd deficiency onto the NOD background provided robust T1D protection, supporting a nonredundant, pathogenic role of gamma delta T cells in this model. The potent contributions of CD27(-) gamma delta T cells and IL-17 to islet inflammation and diabetes reported in this study suggest that these mechanisms may also underlie human T1D.