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

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