A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.
A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.
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DOI：
10.1038/s41385-018-0023-6
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发表时间：
2018-07
影响因子：
8
通讯作者：
Williams CB
中科院分区：
文献类型：
--
作者：
Jeschke JC;Mayne CG;Ziegelbauer J;DeCiantis CL;Singh S;Kumar SN;Suchi M;Iwakura Y;Drobyski WR;Salzman NH;Williams CB
克罗恩病患者的回肠稳态通常会受到破坏，而回肠稳态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有反应的 CD4+T 细胞。在早期，这些小鼠的回肠表现出隐窝增生，并积累了数量增加的带有非转基因克隆型的 TH17 细胞。这些小鼠中有一半随后患上结肠炎，这些结肠炎与表达非转基因克隆型的 TH17 和 TH1 细胞广泛粘膜浸润、慢性消耗性疾病和回肠隐窝增生丧失有关。相比之下，生长正常的成年小鼠继续表现出 TH17 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 积累并加剧结肠炎疾病。 IL-23R 阻断可防止进展为结肠炎，而 nTreg 细胞转移可防止结肠炎疾病、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 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。
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.
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影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
影响因子：
32.4
作者：
Bunker JJ;Flynn TM;Koval JC;Shaw DG;Meisel M;McDonald BD;Ishizuka IE;Dent AL;Wilson PC;Jabri B;Antonopoulos DA;Bendelac A
通讯作者：
Bendelac A
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.
影响因子：
15.9
作者：
Becker, C;Wirtz, S;Neurath, MF
通讯作者：
Neurath, MF
DOI：
10.4049/jimmunol.1301576
发表时间：
2013-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Schmitt EG;Haribhai D;Jeschke JC;Co DO;Ziegelbauer J;Yan K;Iwakura Y;Mishra MK;Simpson P;Salzman NH;Williams CB
通讯作者：
Williams CB