Nature | TCF1 and LEF1 regulate B-1a cell homeostasis and immunomodulatory functions

This study reveals the central role of transcription factors TCF1 and LEF1 in the development and function of B-1a cells, offering new insights into the homeostatic regulation and immunomodulatory mechanisms of innate-like B cells.

 

Literature Overview
This study, titled "TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function" and published in Nature, reviews and summarizes the key roles of TCF1 and LEF1 in maintaining B-1a cell homeostasis and regulatory functions. It also identifies these factors as similarly expressed in human B-1-like cells, providing new molecular targets for mechanistic studies in autoimmune and infectious diseases. Through gene knockout experiments, flow cytometry, RNA-seq, and chromatin analysis, the study systematically elucidates the regulatory network of TCF1–LEF1 in B-1a cells.

Background Knowledge
B-1a cells are innate-like B cells primarily residing in the peritoneal cavity, exerting immunomodulatory and anti-inflammatory effects through molecules like IL-10 and PDL1. They self-renew under homeostatic conditions and migrate to other tissues during infection or inflammation to perform regulatory functions. However, the existence and functional characterization of B-1 cells in humans remain controversial. This study, using murine models and human clinical samples, provides evidence supporting the presence of B-1a cells in humans that express TCF1 and LEF1. The research also highlights that TCF1 and LEF1 maintain self-renewal and metabolic regulation in stem cells and memory T cells, but their role in B cells has been unclear. Currently, the regulatory mechanisms of B-1 cells remain incompletely understood, and their applications in autoimmune and infectious diseases require further exploration. This study addresses these gaps by analyzing TCF1 and LEF1 functions in B-1 cells, offering novel targets for immunomodulatory research.

 

 

Research Methods and Experiments
Researchers analyzed transcriptomic profiles of mouse B-1 cells using scRNA-seq, combined with gene knockout mouse models, flow cytometry, and protein expression detection to define the expression patterns of TCF1 and LEF1 in B-1a cells and their roles in maintaining homeostasis. Additionally, human pleural effusion samples were used to characterize B-1-like cell expression profiles, while BrdU labeling and cell cycle analysis assessed the impact of TCF1–LEF1 deletion on B-1 cell proliferation and exhaustion phenotypes.

Key Conclusions and Perspectives

• TCF1 and LEF1 are highly expressed in mouse B-1a cells, particularly in splenic and peritoneal B-1a cells compared to precursor cells.
• Double knockout of TCF1–LEF1 in mice results in significant reduction of B-1a cell numbers, decreased IL-10 and PDL1 expression, and an exhaustion phenotype.
• Loss of TCF1 and LEF1 impairs B-1 cell self-renewal post-activation and downregulates metabolic and MYC-associated pathways.
• Human B-1-like cells in pleural infection patients show marked expansion and co-expression of TCF1 and LEF1, supporting their immunomodulatory roles.
• B-1 cells from knockout mice fail to suppress central nervous system inflammation after adoptive transfer, indicating TCF1–LEF1-dependent regulatory function.

Research Significance and Prospects
This work establishes TCF1 and LEF1 as critical regulators of B-1a cell homeostasis and function, providing potential molecular targets for treating autoimmune diseases, chronic inflammation, and infections. Future studies should investigate the direct regulatory mechanisms of TCF1–LEF1 in B-1 cell differentiation and function, and explore their expression and functional relevance in human diseases.

 

 

Conclusion
This study systematically identifies TCF1 and LEF1 as key regulators of B-1a cell homeostasis and function. Their deletion leads to reduced B-1a cell numbers, functional exhaustion, and impaired inflammation suppression. Notably, human samples reveal B-1-like cells co-expressing TCF1 and LEF1, particularly in pleural infections and chronic lymphocytic leukemia (CLL). These findings deepen our understanding of the B-1a cell transcriptional regulatory network and provide a theoretical foundation for B cell-targeted therapies and immune homeostasis research. Targeting the TCF1–LEF1 pathway may represent a novel strategy to modulate B-1 cell functions in autoimmune and chronic inflammatory diseases.

 

Qian Shen, Hao Wang, Jonathan A Roco, Nikolaos I Kanellakis, and Carola G Vinuesa. TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function. Nature.