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Significance Immune tolerance is essential to prevent autoimmune responses, but it often needs to be limited for proper immune response. Regulatory T (Treg) cells play a crucial role in immune tolerance; however, their immune-suppressive function is restricted under inflammatory conditions. Here, we show that the activated immune receptor DNAM-1 limits Treg cell function regardless of DNAM-1–mediated intracellular signaling. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to a common ligand. DNAM-1 deficiency enhances TIGIT signaling, thus resulting in the Treg cell function’s maintenance under inflammatory conditions. These results suggest that the DNAM-1 and TIGIT balance orchestrate Treg cell function for optimal immune reaction.

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions