CD40 disruption of autoaggressive (CD4+CD40+) to regulatory (CD4+CD25+FoxP3+) T cell homeostasis promotes diabetes

Abstract

While regulatory T cells (Treg) are well described, identifying autoaggressive effector T cells has proven more difficult. However, we identified CD4loCD40+ (Th40) cells as directly diabetogenic in NOD mice. NOR mice have an identical T cell developmental background, yet are diabetes‐resistant. The BDC2.5.TCR transgenic mouse is on the NOD background; possesses the highly diabetogenic TCR, BDC25; but also is diabetes resistant. The seminal issue is how these mice remain tolerant to self‐antigens. Autoaggressive T cells develop in NOR mice and are confined to the Th40 subset. Interestingly, when Th40 cells and Tregs are depleted, the remaining cells are not diabetogenic, demonstrating that Th40 cells are required for diabetes transfer. We suggest that the determinant factor for autoimmunity is the Th40 to Treg ratio that is significantly disrupted in NOD mice. When compared to BALB/c mice the actual number of Tregs from NOD mice is statistically identical while Treg numbers in NOR or BDC2.5.TCR.Tg mice are slightly higher. The ratio of Th40 cells to Tregs from NOD but not NOR, BALB/c or BDC2.5.TCR.Tg mice is substantially increased. Mechanistically, NOD Th40 cells have low susceptibility to induced cell death and unlike cells from NOR and BALB/c mice, have low Fas expression. CD40 engagement of Th40 cells induces Fas expression but further confers resistance to Fas – mediated cell death in NOD mice. Only at very high Fas concentrations are Th40 cells susceptible to induced cell death. In the BDC2.5.TCR.Tg system we surprisingly found that Th40 cells are abundant but are completely anergic, expressing very high levels of FoxP3. In this instance, these T cells are not typical Tregs, but rather FoxP3 is suppressing the ability of these T cells to be pathogenic.