γδ T cells, a lineage of innate-like lymphocytes, are distinguished from conventional αβ T cells in their antigen-recognition, cell activation requirements and effector functions. γδ 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 γδTCR+ cells including both the CD27−CD44hi and CD27+CD44lo subsets infiltrate islets of pre-diabetic non-obese diabetic (NOD) mice. Moreover, NOD CD27−CD44hi and CD27+CD44lo γδ T cells were pre-programmed to secrete IL-17, or IFN-γ upon activation. Adoptive transfer of T1D to T and B lymphocyte-deficient NOD recipients was greatly potentiated when γδ T cells, and specifically the CD27− γδ T cell subset, were included compared to transfer of αβ T cells alone. Antibody-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 non-redundant, pathogenic role of γδ T cells in this model. The potent contributions of CD27− γδ T cells and IL-17 to islet inflammation and diabetes reported here suggest that these mechanisms may also underlie human T1D.
The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell–restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.
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