The TCR-SUB1-DOCK2 axis promotes autoimmunity by driving pathogenic CD4⁺ T cell tissue infiltration

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Aberrant CD4+ T cell infiltration drives autoimmunity.
• Molecular checkpoints for T cell entry into tissues are poorly understood.

Purpose of the Study:

• Investigate the role of transcription factor SUB1 in T cell migration.
• Identify molecular mechanisms linking T cell activation to tissue infiltration in autoimmunity.

Main Methods:

• Analyzed SUB1 expression in CD4+ T cells from autoimmune patients.
• Utilized conditional gene deletion in T cells.
• Assessed T cell migration, actin polymerization, and experimental autoimmune encephalomyelitis onset.
• Investigated SUB1's role in chromatin accessibility and gene transcription via biomolecular condensates.

Main Results:

• SUB1 is upregulated in CD4+ T cells in autoimmune diseases, induced by TCR-IRF4 signaling.
• Sub1 deletion in T cells reduces DOCK2 expression, impairs T cell motility, and prevents experimental autoimmune encephalomyelitis.
• SUB1 forms biomolecular condensates, opening chromatin at Junb and Dock2 loci.
• SUB1 directly activates Junb and cooperates with JUNB to enhance Dock2 transcription.

Conclusions:

• SUB1 is a key regulator of pathogenic T cell trafficking in autoimmunity.
• The TCR-SUB1-DOCK2 axis represents a potential therapeutic target for autoimmune diseases by modulating T cell migration.