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A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.
Mucosal Immunology ( IF 8 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41385-018-0023-6
Jonathan C Jeschke 1 , Christopher G Mayne 1, 2 , Jennifer Ziegelbauer 1 , Christopher L DeCiantis 1 , Selina Singh 1 , Suresh N Kumar 3 , Mariko Suchi 3 , Yoichiro Iwakura 4, 5 , William R Drobyski 6 , Nita H Salzman 7 , Calvin B Williams 1
Affiliation  

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

中文翻译:

TH17 相关回肠增生模型,需要 IL-17A 和 IFNγ 产生自我耐受并预防结肠炎。

克罗恩病患者通常会破坏回肠中的稳态,这涉及持续的免疫反应。为了研究回肠的稳态过程如何影响 CD4 + T 细胞反应,我们使用 TCR 转基因工具培育小鼠,这些小鼠自发产生对回肠中表达的抗原具有反应性的CD4 + T 细胞。在早期,这些小鼠的回肠表现出隐窝增生并积累了更多数量的带有非转基因克隆型的 T H 17 细胞。这些小鼠中有一半随后发展为结肠炎,这与 T H 17 和 T H广泛的粘膜浸润有关1 细胞表达非转基因克隆型、慢性消耗性疾病和回肠隐窝增生缺失。相比之下,正常生长的成年小鼠继续表现出与 T H 17 相关的回肠隐窝增生,并且还积累了回肠反应性 Treg 细胞。IL-17A 和 IFNγ 均具有保护作用,因为它们的缺乏会阻止回肠反应性 Treg 积聚并加剧结肠炎疾病。IL-23R 阻断阻止了进展为结肠炎,而 nTreg 细胞转移阻止了结肠炎、回肠隐窝增生和回肠反应性 Treg 积聚。因此,我们的研究确定了一个 IL-17A 和 IFNγ 依赖性稳态过程,该过程动员回肠反应性 Treg 细胞并被 IL-23 破坏。
更新日期:2018-05-04
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