Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• FOXP3+ regulatory T cells (Tregs) are essential for maintaining immune tolerance.
• FOXP1 is known to influence Treg function, but FOXP4's role is largely uncharacterized.
• Understanding FOXP family interactions in Tregs is critical for immune regulation.

Purpose of the Study:

• To investigate the functional interactions between FOXP1 and FOXP4 in mouse Treg cells.
• To determine the consequences of combined FOXP1 and FOXP4 deficiency in Tregs.

Main Methods:

• Generation of mouse models with specific genetic deletion of Foxp1, Foxp4, or both in Treg cells.
• Analysis of Treg cell phenotype, suppressive function, and immune responses.
• Investigation of FOXP1 and FOXP4 binding to the Il2ra promoter.

Main Results:

• Combined deficiency of FOXP1 and FOXP4 in Tregs caused lymphoproliferation, inflammation, autoimmunity, and early lethality.
• Absence of both proteins led to an activated Treg phenotype, impaired suppressive function, enhanced germinal center response, and increased proinflammatory cytokine production.
• FOXP1 and FOXP4 were found to regulate CD25 expression by binding to Il2ra promoter regions.

Conclusions:

• FOXP1 and FOXP4 play non-redundant but cooperative roles in Treg cell function.
• FOXP4 has an insufficient role alone, highlighting the importance of FOXP1 in Treg-mediated immune tolerance.
• Combined FOXP1/FOXP4 deficiency severely disrupts Treg function, leading to autoimmune disease.