Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B^N441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b^N440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46⁺ cells in the thymus and reduction in TBR1⁺ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11b^N440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins.

小鼠遗传研究表明，锌指转录因子 BCL11B 在调节早期 T 细胞发育和神经发生中起着重要作用。从一名 T 细胞缺乏症和神经系统疾病患者中分离出一个从头杂合错义 BCL11B 变体 BCL11B^N441K。在这里，我们表明携带相应 Bcl11b^N440K 突变的小鼠在胸腺中出现自然杀伤 （NK）/第 1 组先天淋巴细胞 （ILC1） 样 NKp46 ⁺ 细胞，并在新皮层中减少 TBR1 ⁺ 神经元，这观察到 Bcl11a 丢失但 Bcl11b 没有。因此，突变体 BCL11B-N440K 蛋白在异二聚化时干扰 BCL11A 功能。从机制上讲，Bcl11b^N440K 突变抑制了 BCL11B 与胸腺细胞中 T 细胞因子 1 （TCF1） 的相互作用，导致对支持 NK/ILC1 样细胞分化的 TCF1 活性的拮抗作用减弱。总的来说，我们的结果为 BCL11A 在抑制非 T 淋巴发育潜力中的功能提供了新的思路，并揭示了 BCL11B-N440K 干扰伴侣 BCL11 家族蛋白的致病机制。