Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes

Abstract

Self-reactive Tcells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4+ Tcells despite chronic stimulation. Examination of Tcell priming showed that CD4+ Tcells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new Tcell recruitment, most islet-infiltrating autoimmune CD4+ Tcells were TCF1+, although expression was reduced on a per Tcell basis. The Tcf7 locus was epigenetically modified in circulating autoimmune CD4+ Tcells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4+ Tcell differentiation. This mirrored the epigenetic profile of recently recruited CD4+CD62L+ Tcells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4+ Tcell priming that allows Tcells to fine-tune TCF1 expression and maintain long-term survival and function.