FCRL3 is an immunoregulatory receptor that restrains the activation of human memory T lymphocytes 2328576

Introduction Genetic variants in the FCRL3 gene are associated with multiple autoimmune diseases, yet the function and regulation of FCRL3 in human T lymphocytes remain poorly understood. We aimed to define the cellular identity, regulation, and functional role of FCRL3-expressing human T cells and to elucidate the mechanisms by which FCRL3 modulates T cell responses. Methods We combined multiparametric flow cytometry, transcriptomic analyses, mass spectrometry and functional assays to characterize FCRL3+ human T lymphocytes. FCRL3 expression was analyzed across naïve, memory, and effector T cell subsets. T cell activation, cytokine production, and cytotoxic features were assessed following TCR stimulation. Gain-of-function approaches were used to evaluate the direct impact of FCRL3 expression on T cell responses, and biochemical analyses were performed to investigate associated signaling pathways. Results FCRL3 expression was enriched in cytotoxic CD4+ T cells and CD8+ effector memory TEMRA cells. FCRL3+ T cells displayed a transcriptional program associated with cytotoxicity but showed reduced activation capacity upon TCR engagement. FCRL3 expression was induced by repetitive TCR stimulation and was sufficient to attenuate T cell activation. Mechanistically, the cytoplasmic domain of FCRL3 engaged inhibitory signaling molecules, resulting in dampened downstream TCR signaling. Conclusion Our findings identify FCRL3 as a functional immunoregulatory receptor that restrains activation of highly differentiated human T cells with cytotoxic potential. This work provides mechanistic insight into how genetic associations at the FCRL3 locus may contribute to T cell functions and highlights the importance of inhibitory pathways in maintaining immune balance. Funding Source Swiss National Science Foundation Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)