Department of Immunology, Duke University Medical Center, Durham, NC, United States.
Center for Advanced Genomic Technologies, Duke University, Durham, NC, United States.
Front Immunol. 2020 Mar 31;11:444. doi: 10.3389/fimmu.2020.00444. eCollection 2020.
Foxp3-expressing regulatory T (Treg) cells are critical mediators of immunological tolerance to both self and microbial antigens. Tregs activate context-dependent transcriptional programs to adapt effector function to specific tissues; however, the factors controlling tissue-specific gene expression in Tregs remain unclear. Here, we find that the AP-1 transcription factor JunB regulates the intestinal adaptation of Tregs by controlling select gene expression programs in multiple Treg subsets. Treg-specific ablation of JunB results in immune dysregulation characterized by enhanced colonic T helper cell accumulation and cytokine production. However, in contrast to its classical binding-partner BATF, JunB is dispensable for maintenance of effector Tregs as well as most specialized Treg subsets. In the Peyer's patches, JunB activates a transcriptional program facilitating the maintenance of CD25 Tregs, leading to the complete loss of T follicular regulatory cells in the absence of JunB. This defect is compounded by loss of a separate effector program found in both major colonic Treg subsets that includes the cytolytic effector molecule granzyme B. Therefore, JunB is an essential regulator of intestinal Treg effector function through pleiotropic effects on gene expression.
Foxp3 表达的调节性 T（Treg）细胞是对自身和微生物抗原免疫耐受的关键介质。Tregs 激活与上下文相关的转录程序，使效应功能适应特定组织；然而，控制 Tregs 中组织特异性基因表达的因素仍不清楚。在这里，我们发现 AP-1 转录因子 JunB 通过控制多个 Treg 亚群中的特定基因表达程序来调节 Tregs 的肠道适应性。Treg 特异性敲除 JunB 会导致免疫失调，其特征是结肠 T 辅助细胞积累和细胞因子产生增加。然而，与它的经典结合伴侣 BATF 不同，JunB 对于维持效应 Tregs 以及大多数特化的 Treg 亚群是可有可无的。在派尔氏斑中，JunB 激活了一个转录程序，有助于维持 CD25 Tregs，导致缺乏 JunB 时滤泡性辅助 T 调节细胞完全丧失。这种缺陷因在两个主要结肠 Treg 亚群中发现的另一个效应程序的丧失而加剧，该程序包括细胞毒性效应分子颗粒酶 B。因此，JunB 通过对基因表达的多效性作用成为肠道 Treg 效应功能的必需调节剂。
