Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice.
Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice.
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DOI：
10.4049/jimmunol.1302378
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发表时间：
2014-02-01
期刊：
影响因子：
--
通讯作者：
Suresh M
中科院分区：
文献类型：
--
作者：
Kim EH;Gasper DJ;Lee SH;Plisch EH;Svaren J;Suresh M
Bach 2基因的变异与白癜风、乳糜泻和I型糖尿病有关，但其潜在的免疫机制尚不清楚。在这里，我们证明了Bach 2在维持T细胞静止，并管理foxp 3 + Treg细胞的分化，活化和存活中起着至关重要的作用。Bach 2缺陷型T细胞显示自发活化并产生升高水平的TH 1/TH 2型细胞因子。在没有Bach 2的情况下，Treg细胞表现出减少的foxp 3表达、耗尽的数量、过度活化、增强的增殖和体内竞争适应性的严重丧失。从机制上讲，Bach 2缺陷型Treg细胞的存活率降低与Bcl-2和Mcl-1水平降低以及Bim：Bcl-2比率升高相关。此外，Bach 2缺陷诱导Helios− foxp 3 + Treg细胞的选择性丧失，Treg细胞转录组以Treg程序为代价向TH 1/TH 2效应程序倾斜。体外实验证实Bach 2：（1）对于TCR/TGF-β诱导的foxp 3表达是不可缺少的，并且（2）通过抑制竞争性Gata 3驱动的TH 2效应程序来减轻Treg细胞的异常分化。重要的是，诱导Treg细胞分化的扰动与Bach 2缺陷小鼠中致命的TH 2型慢性炎性肺病有关。因此，Bach 2强制T细胞静止，促进Treg谱系的发育和存活，抑制Treg细胞的异常分化并保护免受免疫介导的疾病。
Variants of the Bach2 gene are linked to vitiligo, celiac disease and type I diabetes, but the underlying immunological mechanisms are unknown. Here, we demonstrate that Bach2 plays crucial roles in maintaining T cell quiescence, and governing the differentiation, activation, and survival of foxp3+ Treg cells. Bach2-deficient T cells display spontaneous activation and produce elevated levels of TH1/TH2 type cytokines. Without Bach2, Treg cells exhibit diminished foxp3 expression, depleted numbers, hyper-activation, enhanced proliferation and profound loss of competitive fitness in vivo. Mechanistically, reduced survival of Bach2-deficient Treg cells was associated with reduced Bcl-2 and Mcl-1 levels and elevated Bim:Bcl-2 ratio. Additionally, Bach2 deficiency induced selective loss of Helios− foxp3+ Treg cells and a Treg cell transcriptome skewed towards the TH1/TH2 effector program at the expense of the Treg program. In vitro experiments confirmed that Bach2: (1) is indispensable for TCR/TGF-β-induced foxp3 expression and (2) mitigates aberrant differentiation of Treg cells by repression of the competing Gata3-driven TH2 effector program. Importantly, perturbations in the differentiation of induced Treg cells was linked to a fatal TH2 type chronic inflammatory lung disease in Bach2-deficient mice. Thus, Bach2 enforces T cell quiescence, promotes the development and survival of Treg lineage, restrains aberrant differentiation of Treg cells and protects against immune -mediated diseases.
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影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
30.5
作者：
Cretney, Erika;Xin, Annie;Kallies, Axel
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Kallies, Axel
影响因子：
30.8
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Jin Y;Birlea SA;Fain PR;Ferrara TM;Ben S;Riccardi SL;Cole JB;Gowan K;Holland PJ;Bennett DC;Luiten RM;Wolkerstorfer A;van der Veen JP;Hartmann A;Eichner S;Schuler G;van Geel N;Lambert J;Kemp EH;Gawkrodger DJ;Weetman AP;Taïeb A;Jouary T;Ezzedine K;Wallace MR;McCormack WT;Picardo M;Leone G;Overbeck A;Silverberg NB;Spritz RA
通讯作者：
Spritz RA
影响因子：
32.4
作者：
Hill JA;Hall JA;Sun CM;Cai Q;Ghyselinck N;Chambon P;Belkaid Y;Mathis D;Benoist C
通讯作者：
Benoist C
影响因子：
29.7
作者：
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通讯作者：
Rudensky AY