The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation.
The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation.
复制标题
DOI：
10.7554/elife.12444
复制
发表时间：
2016-02-24
期刊：
影响因子：
7.7
通讯作者：
Maloy KJ
中科院分区：
文献类型：
--
作者：
Kabat AM;Harrison OJ;Riffelmacher T;Moghaddam AE;Pearson CF;Laing A;Abeler-Dörner L;Forman SP;Grencis RK;Sattentau Q;Simon AK;Pott J;Maloy KJ
自噬基因Atg16l1的多态性与炎症性肠病(IBD)的易感性有关；然而，目前尚不清楚自噬如何有助于肠道免疫动态平衡。在这里，我们证明自噬对于维持肠道内平衡的CD4+T细胞反应是必不可少的。小鼠T细胞中Atg16l1的选择性缺失导致自发性肠炎，其特征是对饮食和微生物区系抗原的2型异常反应，以及Foxp3+Treg细胞的丢失。在小鼠体内对Foxp3+Treg细胞的Atg16l1的特异性消融表明，自噬直接促进了它们在肠道中的存活和代谢适应。此外，我们还发现自噬在直接限制粘膜TH2细胞扩张方面具有意想不到的作用。这些发现为通过自噬相互控制不同的肠道TH细胞反应提供了新的见解，对理解和治疗慢性炎症性疾病具有重要意义。Http://dx.doi.org/10.7554/eLife.12444.001：肠道给我们的免疫系统带来了一个难题。免疫细胞必须对有害细菌产生的抗原迅速做出反应，但食物和肠道中的有益细菌也会产生我们的免疫系统必须耐受的抗原。肠道中不适当的免疫反应会导致炎症性肠病，这是一种目前无法治愈的衰弱疾病。我们不完全理解为什么会出现这些有害的炎症反应，但我们知道遗传因素是重要的。影响自噬过程的基因突变使炎症性肠病更有可能发展为炎症性肠病，但具体是如何做到这一点尚不清楚。自噬是一种途径，可以分解并回收细胞内不需要的物质。T辅助细胞是肠道免疫反应的关键控制细胞，其数量和行为的变化在炎症性肠病期间发生。Kabat等人。探索了自噬途径如何影响小鼠的这些关键免疫细胞。阻断T细胞的自噬改变了肠道中不同类型的T辅助细胞的平衡。控制炎症反应的调节性T细胞的一个关键群体丢失了。与此同时，另一个T细胞群体扩大了：负责驱动过敏的T辅助细胞2(TH2)细胞。结果，小鼠出现了肠道炎症，并产生了针对肠道细菌和食物的抗体。总体而言，卡巴特等人的S的研究结果表明，自噬缺陷会改变肠道中不同类型T细胞的平衡，导致肠道炎症。这些观察有助于我们理解基因变化如何影响炎症性肠病的易感性。他们还表明，激活自噬的药物可能有助于治疗与调节性T细胞或TH2细胞变化相关的疾病，包括炎症性肠病和过敏。现在重要的是测试这一点，并确认在自噬基因发生突变的人类中是否存在类似的T细胞变化。DOI：http://dx.doi.org/10.7554/eLife.12444.002
A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders. DOI: http://dx.doi.org/10.7554/eLife.12444.001 The gut presents a puzzle to our immune system. Immune cells must rapidly respond to antigens produced by harmful bacteria, but food and the beneficial bacteria that inhabit the gut also produce antigens that our immune system must tolerate. Inappropriate immune responses in the gut can lead to inflammatory bowel disease, a debilitating disease with no current cure. We do not fully understand why these harmful inflammatory responses arise, but we know that genetic factors are important. Mutations in genes that affect a process known as autophagy – a pathway that breaks down and recycles unwanted material inside cells – make inflammatory bowel disease more likely to develop, but exactly how they do so remains unclear. T helper cells are crucial controllers of intestinal immune responses and changes in their numbers and behaviour occur during inflammatory bowel disease. Kabat et al. explored how the autophagy pathway affects these key immune cells in mice. Blocking autophagy in T cells altered the balance of different types of T helper cells in the gut. A crucial population of regulatory T cells, which keep inflammatory responses in check, was lost. At the same time, another population of T cells expanded: the T helper 2 (TH2) cells that are responsible for driving allergies. As a result, the mice developed intestinal inflammation and produced antibodies against gut bacteria and food. Overall, Kabat et al.’s results show that autophagy defects can alter the balance of different types of T cells in the gut, leading to inflammation in the intestine. These observations contribute to our understanding of how genetic changes may influence susceptibility to inflammatory bowel disease. They also suggest that drugs that activate autophagy could help to treat diseases associated with changes in regulatory T cells or TH2 cells, including inflammatory bowel disease and allergies. It will now be important to test this and to confirm whether similar changes in T cells are present in humans that have mutations in autophagy genes. DOI: http://dx.doi.org/10.7554/eLife.12444.002