IL-2Rβ-dependent signaling and CD103 functionally cooperate to maintain tolerance in the gut mucosa.
IL-2Rβ-dependent signaling and CD103 functionally cooperate to maintain tolerance in the gut mucosa.
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DOI：
10.4049/jimmunol.1400955
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发表时间：
2015-02-01
期刊：
影响因子：
--
通讯作者：
Malek TR
中科院分区：
文献类型：
--
作者：
Yuan X;Dee MJ;Altman NH;Malek TR
维持肠道黏膜耐受性的机制网络起作用。尽管CD103标记了肠道内的许多淋巴样细胞，但其在肠道耐受中的直接功能作用尚不清楚。CD103可能是冗余途径的一部分，因为CD103−/−小鼠不表现出自身免疫。为了减少这种冗余，将CD103−/−小鼠与T细胞表达IL-2Rβ链的突变小鼠（指定为Y3）杂交，从而降低IL-2R信号传导。与明显健康的Y3小鼠不同，所有的Y3/CD103−/−小鼠都迅速发展为严重的结肠炎。这些小鼠的大肠中含有CD4+ Th1和Th17效应细胞的增加和调节性T细胞（Tregs）的比例降低。重要的是，野生型（WT） Tregs转移到Y3/CD103−/−小鼠中可以有效地预防结肠炎。肠道耐受性受损不是由于明显缺乏CD103依赖性基因调控或Treg的肠道归巢/保留，也不是由于缺乏通常与CD103+树突状细胞（DCs）相关的功能活动，如外周诱导Treg （pTreg）发育或在Treg和T效应细胞上印迹CCR9和α4β7归巢分子。Tregs的转录组分析表明，由于il - 2r β依赖的信号通路受损，体内平衡发生了改变，并且由于缺乏CD103而增加了最小的失调。相反，CD103的缺失改变了细胞在肠道微环境中的定位，从而可能改变Treg稳态。因此，il - 2r β依赖信号和CD103通常通过不同的过程合作，促进Treg稳态和免疫耐受。
A network of mechanisms operates to maintain tolerance in the gut mucosa. Although CD103 marks many lymphoid cells within the gut, its direct functional role in intestinal tolerance is poorly understood. CD103 may be part of a redundant pathway as CD103−/− mice do not exhibit autoimmunity. To reduce such redundancy, CD103−/− mice were crossed to mice (designated Y3) whose T cells expressed a mutant IL-2Rβ chain that lowers IL-2R signaling. Unlike overtly healthy Y3 mice, all Y3/CD103−/− mice rapidly developed severe colitis. The large intestine of these mice contained an increase in CD4+ Th1 and Th17 effector cells and a reduced ratio of regulatory T cells (Tregs). Importantly, colitis was effectively prevented by the transfer of wild type (WT) Tregs into Y3/CD103−/− mice. Impaired intestinal tolerance was not attributed to an obvious lack of CD103-dependent gene regulation or intestinal homing/retention by Tregs nor a lack of functional activities typically associated with CD103+ dendritic cells (DCs), such as peripheral induced Treg (pTreg) development or imprinting CCR9 and α4β7 homing molecules on Treg and T effector cells. Transcriptome analysis of Tregs was consistent with altered homeostasis due to impaired IL-2Rβ-dependent signaling with minimal dysregulation added by the absence of CD103. Rather the absence of CD103 functioned to alter the localization of the cells within the gut microenvironment that may alter Treg homeostasis. Thus, IL-2Rβ-dependent signaling and CD103 normally cooperate through distinctive processes to promote Treg homeostasis and immune tolerance.
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影响因子：
64.8
作者：
CEPEK, KL;SHAW, SK;BRENNER, MB
通讯作者：
BRENNER, MB
影响因子：
64.8
作者：
Esplugues, Enric;Huber, Samuel;Gagliani, Nicola;Hauser, Anja E.;Town, Terrence;Wan, Yisong Y.;O'Connor, William, Jr.;Rongvaux, Anthony;Van Rooijen, Nico;Haberman, Ann M.;Iwakura, Yoichiro;Kuchroo, Vijay K.;Kolls, Jay K.;Bluestone, Jeffrey A.;Herold, Kevan C.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
DOI：
10.4049/jimmunol.1003961
发表时间：
2011-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Castro I;Yu A;Dee MJ;Malek TR
通讯作者：
Malek TR
影响因子：
15.3
作者：
El-Asady, R;Yuan, RW;Hadley, GA
通讯作者：
Hadley, GA
影响因子：
32.4
作者：
Marie, Julien C.;Liggitt, Denny;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.