The TCR-SUB1-DOCK2 Signaling Axis Governs Autoimmunity by Regulating CD4+ T Cell Migratory Capacity

Aberrant activated T cell infiltration is a key driver of autoimmune pathogenesis, highlighting the therapeutic potential of inhibiting T cell migration. However, the regulatory mechanisms governing tissue ingress of antigen-specific T cells remain elusive. Here, we report that SUB1, a transcription factor upregulated in CD4+ T cells from patients with autoimmune disorders, is regulated by the TCR–IRF4 axis. SUB1 deficiency diminished DOCK2 expression by 50%, impairing Rac-dependent actin polymerization and T cell migration, and consequently suppressed the onset of experimental autoimmune encephalomyelitis (EAE). Mechanistically, SUB1 promotes chromatin accessibility at the Junb and Dock2 loci via liquid–liquid phase separation (LLPS), facilitating biomolecular condensate formation. Furthermore, SUB1 directly activates Junb transcription and cooperates with JUNB to enhance Dock2 expression. Our results identify SUB1 as a critical regulator of antigen-specific CD4+ T cell migration and propose it as a promising therapeutic target for autoimmune diseases. Overall design: Histone H3K27ac and H3K4me CHIP-seq analysis using CD4+ T cells isolated from WT and Sub1-KO mice Flag ChIP-seq in OT-II cells overexpressing Flag-SUB1 Flag ChIP-seq following the overexpression of Flag-JUNB in in both WT and Sub1-KO CD4+ T cells