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Lookup NU author(s): Dr Ben Talks, Jason PowellORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial1, 2–3. The CD5+ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory4, 5–6. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal7. Here we show that the transcription factors TCF1 and LEF1 are critical regulators of B-1a cells. LEF1 expression is highest in fetal and bone marrow B-1 progenitors, whereas the levels of TCF1 are higher in splenic and peritoneal B-1 cells than in B-1 progenitors. TCF1–LEF1 double deficient mice have reduced B-1a cells and defective B-1a cell maintenance. These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like population upon activation, partly via IL-10 production. In the absence of TCF1 and LEF1, B-1 cells proliferate excessively and acquire an exhausted phenotype with reduced IL-10 and PDL1 expression. Furthermore, adoptive transfer of B-1 cells lacking TCF1 and LEF1 fails to suppress brain inflammation. These transcription factors are also expressed in human chronic lymphocytic leukaemia B cells and in a B-1-like population that is abundant in pleural fluid and circulation of some patients with pleural infection. Our findings define a TCF1–LEF1-driven transcriptional program that integrates stemness and regulatory function in B-1a cells.
Author(s): Shen Q, Wang H, Roco J, Meng X, Bosticardo M, Hodges M, Battaglia M, Feng Z, Talks B, Powell J, Shanmugiah V, Chu J, Rahman N, Alguili E, Chakravarty P, Grenov A, Emmerich M, Delmonte O, Freeman A, Keller M, Belaid B, Papa I, Lee J, Canete P, Gonzalez-Figueroa P, Zhang Y, Xue H, Turajlic S, Notarangelo L, Haniffa M, Garrett-Sinha L, Parry H, Kanellakis N, Vinuesa C
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2025
Volume: 646
Pages: 442-451
Print publication date: 09/10/2025
Online publication date: 20/08/2025
Acceptance date: 16/07/2025
Date deposited: 01/08/2025
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41586-025-09421-0
DOI: 10.1038/s41586-025-09421-0
Data Access Statement: Data supporting the findings of this study are available within the paper or its supplementary material. Datasets that support the findings of this study are accessible at the following repositories: RNA-seq data (GSE290505), and scRNA-seq and scBCR-seq data (GSE294717 and GSE298030). ChIP–seq and ATAC-seq data were obtained from publicly available datasets (SRP142342 and GSM2461745). Processed and annotated scRNA-seq data of fetal immune cells, specifically the haematopoietic stem and progenitor cells and the B cell lineages in Suo et al.23 were downloaded from the developmental cell atlas portal (https://developmentcellatlas.cellgeni.sanger.ac.uk/fetal-immune/lymphoid/). Source data are provided with this paper. No custom code was used in this study.
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