TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function

Qian Shen (), Hao Wang, Jonathan A. Roco, Xiangpeng Meng, Marita Bosticardo, Marie Hodges, Michael Battaglia, Zhi-Ping Feng, Benjamin James Talks, Jason Powell, Vijaya Baskar Mahalingam Shanmugiah, Julia Chu, Najib M. Rahman, Alguili Elsheikh, Probir Chakravarty, Amalie Grenov, Max Emmerich, Ottavia M. Delmonte, Alexandra F. Freeman, Michael D. Keller, Brahim Belaid, Ilenia Papa, James C. Lee, Pablo F. Cañete, Paula Gonzalez-Figueroa, Yaoyuan Zhang, Hai-Hui Xue, Samra Turajlic, Luigi D. Notarangelo, Muzlifah Haniffa, Lee Ann Garrett-Sinha, Helen M. Parry, Nikolaos I. Kanellakis and Carola G. Vinuesa ()
Additional contact information
Qian Shen: Francis Crick Institute
Hao Wang: Francis Crick Institute
Jonathan A. Roco: Francis Crick Institute
Xiangpeng Meng: Australian National University
Marita Bosticardo: National Institutes of Health
Marie Hodges: University of Birmingham
Michael Battaglia: State University of New York at Buffalo
Zhi-Ping Feng: Australian National University
Benjamin James Talks: Newcastle University
Jason Powell: Newcastle upon Tyne Hospitals NHS Foundation Trust
Vijaya Baskar Mahalingam Shanmugiah: Wellcome Genome Campus
Julia Chu: University of Oxford
Najib M. Rahman: Oxford University Hospitals NHS Foundation Trust
Alguili Elsheikh: Oxford University Hospitals NHS Foundation Trust
Probir Chakravarty: Francis Crick Institute
Amalie Grenov: Francis Crick Institute
Max Emmerich: Francis Crick Institute
Ottavia M. Delmonte: National Institutes of Health
Alexandra F. Freeman: National Institutes of Health
Michael D. Keller: Children’s National Hospital
Brahim Belaid: University of Algiers
Ilenia Papa: Francis Crick Institute
James C. Lee: Francis Crick Institute
Pablo F. Cañete: The University of Queensland
Paula Gonzalez-Figueroa: Francis Crick Institute
Yaoyuan Zhang: Australian National University
Hai-Hui Xue: Hackensack University Medical Center
Samra Turajlic: Francis Crick Institute
Luigi D. Notarangelo: National Institutes of Health
Muzlifah Haniffa: Wellcome Genome Campus
Lee Ann Garrett-Sinha: State University of New York at Buffalo
Helen M. Parry: University of Birmingham
Nikolaos I. Kanellakis: University of Oxford
Carola G. Vinuesa: Francis Crick Institute

Nature, 2025, vol. 646, issue 8084, 442-451

Abstract: Abstract 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 controversial1–3. The CD5+ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory4–6. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09421-0

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