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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• B-1 cells, particularly the CD5+ B-1a subset, are innate-like immune cells with immunoregulatory functions, expressing anti-inflammatory molecules like IL-10.
• Unlike conventional B cells, B-1a cells are established early in life and self-renew, but their precise regulation remains incompletely understood.

Purpose of the Study:

• To investigate the role of transcription factors TCF1 and LEF1 in the regulation and function of B-1a cells.
• To elucidate the molecular mechanisms by which TCF1 and LEF1 control B-1a cell stemness and regulatory properties.

Main Methods:

• Analysis of TCF1 and LEF1 expression in B-1 cell progenitors and mature B-1 cells from mice.
• Generation and analysis of TCF1-LEF1 double-deficient mice to assess B-1a cell populations and function.
• Investigating the impact of TCF1 and LEF1 deficiency on B-1 cell metabolism, stemness, and IL-10 production.
• Adoptive transfer experiments to evaluate the immunoregulatory capacity of TCF1/LEF1-deficient B-1 cells in a model of brain inflammation.

Main Results:

• TCF1 and LEF1 are critical regulators of B-1a cell development and maintenance, with distinct expression patterns in progenitors versus mature cells.
• TCF1-LEF1 deficiency leads to reduced B-1a cell numbers, impaired self-renewal, and defective expression of IL-10 and PDL1.
• These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like phenotype in activated B-1a cells.
• B-1 cells lacking TCF1 and LEF1 exhibit excessive proliferation, an exhausted phenotype, and fail to suppress experimental brain inflammation.

Conclusions:

• A TCF1-LEF1-driven transcriptional program is essential for integrating stemness and regulatory functions in B-1a cells.
• These findings highlight the importance of TCF1 and LEF1 in maintaining B-1a cell homeostasis and their immunoregulatory potential.
• The study identifies TCF1 and LEF1 as key players in B-1a cell biology with implications for understanding immune regulation and diseases like chronic lymphocytic leukemia.