FCRL3 is an immunoregulatory receptor that restrains the activation of human memory T lymphocytes.

Genetic variants in the FCRL3 gene are linked to autoimmune disorders. However, the functional properties of FCRL3-expressing T lymphocytes, and the regulation and functional impact of FCRL3 expression remain understudied. Here, we performed a multiomic and functional analysis of human T lymphocytes expressing FCRL3. FCRL3 expression correlated with reduced capacity of T cells to undergo activation and was accompanied by functional specialization toward a cytotoxic phenotype, resembling cytotoxic CD4+ T lymphocytes and CD8+ effector memory TEMRA cells. FCRL3 expression was induced upon repetitive TCR engagement, and sufficed to attenuate T cell responses, indicating a role as a negative regulator of the activation of differentiated T cell subsets with high cytotoxic capacity. Mechanistically, the cytoplasmic domain of FCRL3 engaged inhibitory molecules, suggesting a direct role in limiting activating signals. Overall, our study establishes FCRL3 as a functional immunoregulatory receptor that restrains the activation of highly specialized human memory T cells.