The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma.

转录因子 Foxp1 对早期 B 细胞发育至关重要。尽管在 B 细胞淋巴瘤中 Foxp1 经常失调，但 Foxp1 在成熟 B 细胞中的生理功能仍然未知。在这里，我们在 B 细胞谱系中使用条件基因靶向，并报告 Foxp1 在发育和成熟 B 细胞中的破坏导致滤泡和 B-1 B 细胞的数量和频率减少，并且在体内不依赖 T 细胞的免疫接种时抗体产生受损. 此外，Foxp1 缺陷型 B 细胞的存活受到损害，即使它们表现出增加的增殖能力。转录分析确定了 prosurvival Bcl-2 家族基因Bcl2l1的缺陷表达在 Foxp1 缺陷 B 细胞中编码 Bcl-xl，我们在Bcl2l1的调节区鉴定了 Foxp1 结合。Bcl2 的转基因过表达挽救了体内Foxp1 缺陷成熟B 细胞的存活缺陷并恢复了外周B 细胞数量。因此，我们的结果将 Foxp1 鉴定为成熟 B 细胞存活的生理调节剂，部分通过控制 Bcl-xl 表达介导，并暗示该途径可能有助于淋巴瘤中异常 Foxp1 表达的致病功能。