Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, 53706 WI, USA.
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, 53706 WI, USA.
J Immunol Res. 2022 Aug 5;2022:6789055. doi: 10.1155/2022/6789055. eCollection 2022.
FoxP3+ regulatory T cells (Tregs) are essential for self-tolerance and moderating tissue-damaging inflammation. Tregs that develop and mature in the thymus are classified as central Tregs or effector Tregs based on whether Tregs predominately inhabit secondary lymphoid organs (central Tregs) or tissues (effector Tregs). By generating mice that are conditionally deficient for Bach2 in peripheral Tregs, we have examined the role of Bach2 in regulating Treg homeostasis and effector functions. Unlike global and T cell-specific Bach2-deficient mice, Treg-specific Bach2 ablation did not result in unprovoked T2 inflammation in the lungs. However, Bach2 deficiency in Tregs led to augmented expressions of IRF4, BATF, and GATA3 and a significant increase in the accumulation of ST2 (IL-33R) effector Tregs in the spleen and visceral adipose tissue (VAT) but not in the lungs. Enhanced Bach2-deficient Treg numbers in VAT was not linked to hyperresponsiveness to exogenous IL-33 in vivo. Most strikingly, Treg-specific Bach2 deficiency resulted in enhanced fungal protease-induced Type 2 allergic inflammation in the lungs, with no detectable effects on Type 1 responses to systemic or respiratory viral infections. In summary, we ascribe vital roles for Bach2 in peripheral Tregs: as a transcriptional checkpoint to limit precocious differentiation into effector Tregs in lymphoid tissues and as a regulator of the functional program that restrains Type 2 but not Type 1 inflammation in lungs. Results presented in this manuscript implicate dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.
FoxP3+ 调节性 T 细胞（Tregs）对于自身耐受和调节组织损伤性炎症至关重要。在胸腺中发育和成熟的 Tregs 根据其主要栖息于次级淋巴器官（中央 Tregs）还是组织（效应 Tregs），被分类为中央 Tregs 或效应 Tregs。通过生成外周 Tregs 条件性 Bach2 缺陷的小鼠，我们研究了 Bach2 在调节 Treg 稳态和效应功能中的作用。与全局和 T 细胞特异性 Bach2 缺陷小鼠不同，Treg 特异性 Bach2 缺失不会导致肺部自发的 T2 炎症。然而，Tregs 中的 Bach2 缺失导致 IRF4、BATF 和 GATA3 的表达增强，并且 ST2（IL-33R）效应 Tregs 在脾脏和内脏脂肪组织（VAT）中的积累显著增加，但在肺部没有增加。VAT 中增强的 Bach2 缺陷 Treg 数量与体内对外源 IL-33 的超反应性无关。最引人注目的是，Treg 特异性 Bach2 缺失导致肺部真菌蛋白酶诱导的 2 型过敏炎症增强，而对系统性或呼吸道病毒感染的 1 型反应没有可检测到的影响。总之，我们认为 Bach2 在外周 Tregs 中发挥重要作用：作为一个转录检查点，限制其在淋巴组织中过早分化为效应 Tregs；作为一个调节功能程序的调节剂，限制肺部的 2 型炎症但不限制 1 型炎症。本研究结果提示 Tregs 失调在气道高反应性、哮喘和其他过敏疾病的发病机制中起作用。
