Shen Qian, Wang Hao, Roco Jonathan A, Meng Xiangpeng, Bosticardo Marita, Hodges Marie, Battaglia Michael, Feng Zhi-Ping, Talks Benjamin James, Powell Jason, Shanmugiah Vijaya Baskar Mahalingam, Chu Julia, Rahman Najib M, Elsheikh Alguili, Chakravarty Probir, Grenov Amalie, Emmerich Max, Delmonte Ottavia M, Freeman Alexandra F, Keller Michael D, Belaid Brahim, Papa Ilenia, Lee James C, Cañete Pablo F, Gonzalez-Figueroa Paula, Zhang Yaoyuan, Xue Hai-Hui, Turajlic Samra, Notarangelo Luigi D, Haniffa Muzlifah, Garrett-Sinha Lee Ann, Parry Helen M, Kanellakis Nikolaos I, Vinuesa Carola G
Francis Crick Institute, London, UK.
Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09421-0.
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 controversial. The CD5 B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal. 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.
B-1细胞是一种固有样免疫细胞，在浆膜腔中大量存在，其抗体富含细菌识别功能，但它们在人类中的存在一直存在争议。CD5 B-1a亚群表达包括IL-10、PDL1和CTLA4在内的抗炎分子，具有免疫调节作用。与不断补充的传统B细胞不同，B-1a细胞在生命早期产生，并通过自我更新维持。我们发现转录因子TCF1和LEF1是B-1a细胞的关键调节因子。LEF1在胎儿和骨髓B-1祖细胞中表达最高，而TCF1在脾脏和腹膜B-1细胞中的水平高于B-1祖细胞。TCF1-LEF1双缺陷小鼠的B-1a细胞减少，B-1a细胞维持存在缺陷。这些转录因子促进MYC依赖性代谢途径，并在激活时诱导出一种干细胞样群体，部分是通过产生IL-10。在缺乏TCF1和LEF1的情况下，B-1细胞过度增殖并获得一种耗竭表型，IL-10和PDL1表达降低。此外，缺乏TCF1和LEF1的B-1细胞的过继转移不能抑制脑部炎症。这些转录因子也在人类慢性淋巴细胞白血病B细胞以及一些胸膜感染患者胸腔积液和循环中丰富的B-1样群体中表达。我们的研究结果定义了一个由TCF1-LEF1驱动的转录程序，该程序整合了B-1a细胞的干性和调节功能。
