BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
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通过功能的多样化，不同的CD4+T细胞在驱动或抑制免疫介导的病理过程中发挥着关键作用。转录因子在细胞多样性的产生中是至关重要的，而对交替命运具有拮抗作用的负调控因子经常与正调控因子一起作用，以稳定谱系承诺。编码转录因子BACH2的单个基因座内的基因多态性与许多自身免疫性和过敏性疾病有关，包括哮喘、克罗恩病、乳糜泻、白癜风、多发性硬化症和1型糖尿病。虽然这些关联表明对不同的免疫介导性疾病的易感性存在共同的机制，但Bach2在维持免疫动态平衡方面的功能尚未建立。在这里，我们将Bach2定义为一种广泛的免疫激活调节因子，它在稳定免疫调节能力的同时抑制CD4+T细胞中多个效应细胞系的分化程序。Bach2是有效形成调节性(Treg)细胞所必需的，从而以Treg细胞依赖的方式抑制致死性炎症。然而，对Bach2全基因组功能的评估显示，它抑制了与效应细胞分化相关的基因。因此，它在Treg极化期间的缺失导致不适当地转移到效应器谱系。此外，Bach2抑制了Th1、Th2和Th17细胞系内的完全效应器分化。这些发现确定Bach2是CD4+T细胞分化的关键调节因子，通过控制耐受和免疫之间的平衡来预防炎症性疾病。
Through their functional diversification, distinct lineages of CD4+ T cells play key roles in either driving or constraining immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn’s disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. While these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for Bach2 in the maintenance of immune homeostasis has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.