It is well established that CD4 and CD8 T cells are required for the initiation of autoimmune diabetes in NOD mice. However, different subsets of CD4 or CD8 cells may play different roles in the initiation of insulitis. In this study, we evaluated the role of the previously described CD8(+) CD122(+) in this process. We found that prediabetic NOD mice have an almost 50% reduction of CD8(+) CD122(+) T cells in their secondary lymphoid organs compared with BL/6 or Balb/c mouse strains. This reduction is explained by the lack of the regulatory CD8(+) CD122(+) PD-1(+) cell population in the NOD mice, as we found that all CD8(+) CD122(+) T cells from prediabetic NOD mice lack PD-1 expression and regulatory function. Depletion of CD8(+) CD122(+) PD-1(-) cells through injection of anti-CD122 mAb in prediabetic female NOD mice reduced the infiltration of mononuclear cells into the Langerhans islets and delayed the onset and decreased the incidence of overt diabetes. In addition, we found that transfer of highly purified and activated CD8(+) CD122(+) PD-1(-) cells, together with diabetogenic splenocytes from NOD donors to NOD SCID recipients, accelerates the diabetes development in these mice. Together, these results demonstrate that CD8(+) CD122(+) PD-1(-) T cells from NOD mice are effector cells that are involved in the pathogenesis of autoimmune diabetes.

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