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.
Authors
- David Jarrossay (ORCID: https://orcid.org/0000-0002-0924-6395)
- Roshan Singh Thakur (ORCID: https://orcid.org/0000-0001-5284-4975)
- Matteo Pecoraro (ORCID: https://orcid.org/0009-0002-8105-9671)
- Silvia Monticelli (ORCID: https://orcid.org/0000-0002-5909-8802)
- Mara Cetty Spinella (ORCID: https://orcid.org/0000-0002-2363-3295)
- Federica Sallusto (ORCID: https://orcid.org/0000-0003-3750-2752)
- Niccolò Bianchi (ORCID: https://orcid.org/0000-0001-5605-3425)
- Sara Polletti (ORCID: https://orcid.org/0000-0002-5433-0502)
- Elena Foli
- Gioacchino Natoli (ORCID: https://orcid.org/0000-0003-0711-2411)
- Antonino Cassotta (ORCID: https://orcid.org/0000-0001-8674-4294)
- Roberta Marzi (ORCID: https://orcid.org/0000-0002-3501-4168)
- Mehrpouya Mostanfar (ORCID: https://orcid.org/0000-0003-2624-7063)
Institutions
- ETH Zurich (CH)
- Institute for Biomedical Engineering (CH)
- Università della Svizzera italiana (CH)
- European Institute of Oncology (IT)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-10-15
- DOI
- https://doi.org/10.1084/jem.20242474
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- National Science Foundation
- University of Bern
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Ministero della Salute