CD40 engagement of CD4+ CD40+ T cells in a neo-self antigen disease model ablates CTLA-4 expression and indirectly impacts tolerance

Biomarkers defining pathogenic effector T (Teff) cells slowly have been forthcoming and towards this we identified CD4+ T cells that express CD40 (CD4+CD40+) as pathogenic in the NOD type 1 diabetes (T1D) model. CD4+CD40+ T cells rapidly and efficiently transfer T1D to NOD.scid recipients. To study the origin of CD4+CD40+ T cells and disease pathogenesis, we employed a dual transgenic model expressing OVA(323-339) peptide as a neo-self antigen on islet beta cells and medullary thymic epithelial cells (mTECs) and a transgenic TCR recognizing the OVA(323-339) peptide. CD4+CD40+ T cells and Treg cells each recognizing the cognate neo-antigen, rather than being deleted through central tolerance, drastically expanded in the thymus. In pancreatic lymph nodes of DO11.RIPmOVA mice, CD4+CD40+ T cells and Treg cells are expanded in number compared with DO11 mice and importantly, Treg cells remain functional throughout the disease process. When exposed to neo-self antigen, CD4+CD40+ T cells do not express the auto-regulatory CTLA-4 molecule while naive CD4+CD40+ T cells do. DO11.RIPmOVA mice develop autoimmune-type diabetes. CD40 engagement has been shown to prevent CTLA-4 expression and injecting anti-CD40 in DO11.RIPmOVA mice significantly exacerbates disease. These data suggest a unique means by which CD4+CD40+ T cells thwart tolerance.