Tregs suppress CD8 T cell effector function in inflamed tissue in a mouse model of autoimmune diabetes (P1018)

Abstract

Abstract The aim of this study was to determine the means by which Tregs control disease in the NOD mouse model of autoimmune diabetes. Treatment of pre-diabetic mice with ongoing islet destruction with islet antigen-specific Tregs expanded from BDC2.5 TCR transgenic mice led to a rapid restoration of insulin production and a concomitant selective downregulation of a cytotoxic T lymphocyte signature, which included CD8α, IFNγ, granzymes A and B, and Cxcl9. This downregulation could be partially attributed to a decrease in intra-islet CD8 T cell numbers due to impaired recruitment of CD8 T cells to the islets. In addition, Treg treatment also reduced effector function of persisting CD8 T cells. Two-photon imaging showed that Tregs did not significantly disrupt interactions between islet CD8 T cells and dendritic cells, but abrogated IFNγ production by CD8 T cells. This suppression appeared to take place at multiple stages of CD8 T cell differentiation. Tregs inhibited differentiation of newly recruited CD8 T cells to IFNγ producers completely, but prevented IFNγ protein expression without affecting IFNγ message in pre-activated CD8 T cells. Altogether, these results indicate that CD8 T cells are the primary early targets of Treg control of tissue inflammation and rapid disease resolution by Tregs can be attributed to efficient control of CD8 T cell infiltration, reactivation in the tissue, and their expression of effector functions.