Human Fc Receptor-like 3 Inhibits Regulatory T Cell Function and Binds Secretory IgA

Human Fc receptor-like 3 (FCRL3) is an orphan receptor expressed by lymphocytes, including regulatory T cells. FCRL3 is implicated in several autoimmune diseases; however, its function on regulatory T cells is unknown. We discovered that FCRL3 stimulation of regulatory T cells inhibited their suppressive function. Moreover, FCRL3 stimulation induced IL-17, IL-26, and IFNγ production and promoted expression of the Th17-defining transcription factor RORγt without affecting FOXP3 expression. We suggest that FCRL3 engagement mediates a transition of regulatory T cells to a pro-inflammatory Th17-like phenotype. In addition, we identified secretory IgA as a specific FCRL3 ligand. Secretory IgA could serve as an environmental cue for mucosal breaches and locally drive regulatory T cell plasticity to help control infection. Our findings define a mechanism that explains the recognized association of FCRL3 with autoimmune diseases. Targeting FCRL3 to modulate regulatory T cell activity could be exploited to treat both malignancies and autoimmune diseases.