| First Author | Carter J | Year | 2012 |
| Journal | Eur J Immunol | Volume | 42 |
| Issue | 2 | Pages | 424-35 |
| PubMed ID | 22105491 | Mgi Jnum | J:179815 |
| Mgi Id | MGI:5304211 | Doi | 10.1002/eji.201141880 |
| Citation | Carter J, et al. (2012) CD40 engagement of CD4(+) CD40(+) T cells in a neo-self antigen disease model ablates CTLA-4 expression and indirectly impacts tolerance. Eur J Immunol 42(2):424-35 |
| abstractText | 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. |
