DM functions differently in thymic antigen presentation cell subsets in development of autoreactive CD4+ T cells

Abstract

Abstract Autoreactive CD4+ T cells broadly exist in healthy individuals and potentially cause autoimmune diseases; however, why they can escape from thymic negative selection is still controversial. We observed that the activity of DM, a peptide epitope editor in MHC class II antigen presentation pathway, is differentially regulated in different thymic antigen presenting cells (APC). It is high in cTEC that involved in cortical positive selection, but low in mTEC, B cell, pDC and cDC that mediate negative selection in medulla, while it remains high in all types of peripheral APC. The molecular mechanism of differential regulation is still unknown. It is not directly inhibited by DO, a negative regulator of DM that directly competes DM catalytic site with peptide-MHC class II complex, since DM editing activity remains low in those thymic medulla APC in DO−/− mice. We further confirmed that presentation of autoantigen epitope MOG35–55 for thymic positive selection and in vitro activation of autoreactive CD4+ T cells in EAE, a mouse model of human multiple sclerosis disease, is DM dependent. This is also true for presentation of insulin epitope B9–23 to activate autoreactive CD4+ T cells restricted to type 1 diabetes associated HLA-DQ8. Our findings highlighted a fundamental mechanism that immune system differentially regulates DM activity in thymus to balance the efficiency of negative selection to minimize autoimmunity and the maximum of T cell repertoire to defend infection; however, the DM-dependency property of certain autoantigen epitopes accidently caused the failure deletion of autoreactive CD4+ T cells.