title: CD40 engagement of CD4+ CD40+ T cells in a neo-self antigen disease model ablates CTLA-4 expression and indirectly impacts tolerance.
abstract: 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 β 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 naïve 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.
authors: The Webb-Waring Center, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors: Jessica
authors: J
authors: Carter
authors: Gisela M
authors: GM
authors: Vaitaitis
authors: Dan M
authors: DM
authors: Waid
authors: David H
authors: DH
authors: Wagner
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D056747:Immunomodulation; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology
chemical_list: D001324:Autoantigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen