A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that <b>γδ</b> T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their <b>γδ</b> T cell populations, and by investigating the functional contributions of particular <b>γδ</b> T cells subsets, using V<b>γ</b>-gene targeted NOD mice. We found evidence that NOD V<b>γ</b>4+ <b>γδ</b> T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes. In contrast, the NOD V<b>γ</b>1+ cells promote diabetes development. Enhanced V<b>γ</b>1+ cell numbers in NOD mice, in particular those biased to produce IFN<b>γ</b>, appear to favor diabetic disease. Within NOD mice deficient in particular <b>γδ</b> T cell subsets, we noted that changes in the abundance of non-targeted T cell types also occurred, which varied depending upon the <b>γδ</b> T cells that were missing. Our results indicate that while certain <b>γδ</b> T cell subsets inhibit the development of spontaneous type 1 diabetes, others exacerbate it, and they may do so via mechanisms that include altering the levels of other T cells.