英国弗朗西斯克里克研究所Carola G. Vinuesa小组宣布他们的最新研究探明了TCF1和LEF1促进B-1a细胞稳态和调控功能。该研究于2025年8月20日发表于国际一流学术期刊《自然》杂志上。

该课题组发现转录因子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在脾和腹膜B-1细胞中的表达高于B-1祖细胞。TCF1-LEF1双缺陷小鼠B-1a细胞减少，B-1a细胞维持缺陷。这些转录因子促进MYC依赖的代谢途径，并在激活后部分通过IL-10的产生诱导茎样群体。在缺乏TCF1和LEF1的情况下，B-1细胞过度增殖并获得衰竭表型，IL-10和PDL1表达降低。

此外，缺乏TCF1和LEF1的B-1细胞过继转移不能抑制脑炎症。这些转录因子也在人慢性淋巴细胞白血病B细胞中表达，并在一些胸膜感染患者的胸膜液和循环中丰富的b1样群体中表达。他们的发现定义了一个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。

据悉，B-1细胞是存在于浆膜腔内的先天免疫细胞，具有丰富的细菌识别抗体，但其在人体中的存在一直存在争议。CD5⁺ B-1a亚群表达抗炎分子，包括IL-10、PDL1和CTLA4，并具有免疫调节作用。与不断补充的传统B细胞不同，B-1a细胞在生命早期产生，并通过自我更新来维持。

附：英文原文

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

Author: 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., Caete, 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.

Issue&Volume: 2025-08-20

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 controversial1,2,3. 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.

DOI: 10.1038/s41586-025-09421-0

Source: https://www.nature.com/articles/s41586-025-09421-0