IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.,Mucosal Immunology

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IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2018-Dec-12 , DOI: 10.1038/s41385-018-0118-0
L M M Costes ₁ , D J Lindenbergh-Kortleve ₁ , L A van Berkel ₁ , S Veenbergen ₁ , H R C Raatgeep ₁ , Y Simons-Oosterhuis ₁ , D H van Haaften ₁ , J J Karrich ₂ , J C Escher ₃ , M Groeneweg ₄ , B E Clausen ₅ , T Cupedo ₂ , J N Samsom ₁

Affiliation

Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4⁺CD8αα⁺ IEL (CD4⁺ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4⁺CD8α^- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B⁺CD4⁺CD8α⁺ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4⁺ CTL are potential new players into these processes.

中文翻译：

IL-10 信号可防止小肠中的麸质依赖性上皮内 CD4+ 细胞毒性 T 淋巴细胞浸润和上皮损伤。

违反对麸质的耐受性会导致慢性小肠肠病腹腔疾病。乳糜泻发展中的一个关键事件是活化的细胞毒性上皮内淋巴细胞 (IEL) 的麸质依赖性浸润，它会溶解上皮细胞，导致隐窝增生和绒毛萎缩。导致麸质依赖性小肠 IEL 浸润和激活的机制仍然难以捉摸。我们已经证明，在小鼠的稳态条件下，麸质会促进抗炎 T 细胞的分化，从而产生大量免疫抑制细胞因子白细胞介素 10 (IL-10)。在这里，我们讨论了这种占主导地位的 IL-10 轴是否可以防止激活的细胞毒性 IEL 的麸质依赖性浸润和随后的小肠肠病。我们证明 IL-10 调节可防止麸质诱导的细胞毒性炎症 IEL 浸润。特别是，IL-10 抑制面筋诱导的特定细胞毒性 CD4 群体的积累⁺ CD8αα ⁺ IEL (CD4 ⁺ CTL) 表达 Tbx21、Ifng 和 Il21，以及不同的非细胞溶解性 CD4 ⁺ CD8α ^- IEL 群体表达 Il17a、Il21 和 Il10。同时，IL-10 抑制麸质依赖性小肠上皮过度增殖和上皮细胞上应激诱导分子的上调。值得注意的是，在小儿乳糜泻患者活组织检查中，颗粒酶 B ⁺ CD4 ⁺ CD8α ^{+ IEL 的频率增加。}这些发现表明 IL-10 是预防麸质诱导的小肠炎症和上皮损伤的关键，并暗示 CD4 ⁺ CTL 是这些过程中潜在的新参与者。

更新日期：2019-01-26

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