γδ T Cell-Secreted XCL1 Mediates Anti-CD3-Induced Oral Tolerance

Area of Science:

• Immunology
• Gastroenterology
• Cellular Biology

Background:

• Oral tolerance suppresses immune responses to antigens administered orally.
• Oral administration of anti-CD3 monoclonal antibody (mAb) induces tolerance via regulatory T (Treg) cell generation, but mechanisms are unclear.

Purpose of the Study:

• To elucidate the mechanisms underlying anti-CD3 mAb-induced oral tolerance.
• To investigate the roles of dendritic cells and T cells in this process.
• To explore the potential of anti-CD3 mAb as an adjuvant for oral tolerance induction.

Main Methods:

• Utilized anti-CD3 mAb administration in mouse models.
• Investigated the requirement of conventional and plasmacytoid dendritic cells (DCs).
• Analyzed XCL1 secretion by γδ T cells and XCR1+ DC migration.
• Assessed oral tolerance induction in TCRδ-/- mice and experimental autoimmune encephalomyelitis (EAE) models.

Main Results:

• Conventional DCs, not plasmacytoid DCs, are essential for anti-CD3-induced oral tolerance.
• Oral anti-CD3 promotes XCL1 secretion by intestinal γδ T cells, driving tolerogenic DC migration and Treg cell induction.
• TCRδ-/- mice failed to develop oral tolerance to anti-CD3.
• XCL1 is not required for antigen-induced oral tolerance.
• Oral anti-CD3 enhanced MOG35-55 peptide-induced oral tolerance, reducing EAE severity.

Conclusions:

• Treg cell induction by oral anti-CD3 results from crosstalk between γδ T cells and tolerogenic DCs in the gut.
• This mechanism differs from that of antigen feeding-induced oral tolerance.
• Anti-CD3 mAb can act as an adjuvant to enhance oral tolerance to fed antigens.