GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development.

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Regulatory T cells (Tregs) are crucial for immune homeostasis and preventing autoimmunity.
• Peripheral Treg differentiation is influenced by gut microbiota metabolites acting via G-protein-coupled receptors (GPCRs) like GPR109A.
• The role of GPR109A in central Treg development within the thymus was previously unknown.

Purpose of the Study:

• To investigate the novel role of GPR109A in thymic Treg development.
• To determine the cellular expression and function of GPR109A in the thymus.
• To assess the impact of GPR109A deficiency on autoimmune disease models.

Main Methods:

• Single-cell RNA sequencing in mice and humans to identify GPR109A expression.
• Flow cytometry in mice to confirm GPR109A expression on thymic cells.
• Analysis of Treg cell populations and autoimmune regulator (AIRE) expression in Gpr109a knockout (Gpr109a-/-) and wild-type (WT) mice.
• Assessment of experimental autoimmune encephalomyelitis (EAE) in Gpr109a-/- mice.

Main Results:

• Gpr109a-/- mice exhibited increased Treg cells in multiple organs under basal conditions compared to WT mice.
• GPR109A is expressed on medullary thymic epithelial cells (mTECs), not T cells.
• mTECs from Gpr109a-/- mice showed higher AIRE expression; WT mTECs lacking GPR109A also had increased AIRE and enhanced functionality.
• Increased thymic Treg in Gpr109a-/- mice conferred protection against EAE, with reduced clinical signs and inflammation.

Conclusions:

• GPR109A plays a novel inhibitory role in thymic Treg development by regulating mTEC function and AIRE expression.
• The gut microbiota may influence thymic Treg development through GPR109A signaling on mTECs.
• Targeting GPR109A could be a therapeutic strategy for autoimmune diseases.