SUB1-DOCK2 axis dictates autoimmunity by controlling the migration of self-reactive CD4+ T cells 3038

Description The migration of abnormally activated T cells into target tissues is a critical determinant of the pathological outcomes, suggesting that the blockade of T cell trafficking presents a promising therapeutic strategy to mitigate autoimmunity. However, the intricate mechanisms governing tissue infiltration of self-reactive T-cells remain poorly understood. Here, we found a high expression level of transcription factor SUB1 in CD4+ T cells under the conditions of human autoimmune diseases, and the Sub1 expression is driven by the TCR-IRF4 pathway. The absence of SUB1 leads to down-regulation of Dock2 expression in CD4+ T cells, thereby inhibiting RAC activation and F-actin polymerization, ultimately suppressing the migration of self-reactive CD4+ T cells and preventing the occurrence of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 directly promotes the transcriptional expression of Junb. Meanwhile, SUB1 enhances the accessibility of the Dock2 locus through modifications of H3K27ac and H3K4me1, thereby facilitating the recruitment of JUNB to both enhancer and promoter regions to induce Dock2 gene expression. In summary, our study highlights SUB1 as a crucial regulator of self-reactive CD4+ T cell migration, presenting it as a novel therapeutic target for the intervention in autoimmune diseases.