T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice
T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice
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DOI：
10.1053/gast.2003.50092
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发表时间：
2003-03-01
期刊：
影响因子：
29.4
通讯作者：
McGhee, JR
中科院分区：
文献类型：
--
作者：
Dohi, T;Fujihashi, K;McGhee, JR
背景与目的：辅助性T细胞（Th）1和Th2细胞亚群以截然不同的方式显著影响胃肠道炎症的病理特征。现已证实，将CD4(+)CD45RB(高)（RBHi）T细胞转移至重症联合免疫缺陷（SCID）或重组酶激活基因2缺陷（RAG(-/-)）小鼠体内，会导致由Th1细胞介导的严重肉芽肿性肥厚性结肠炎。我们对这一方法进行了改进以探究Th2细胞的作用。
方法：将来自野生型（Wt）小鼠或具有Th2反应遗传倾向的小鼠（干扰素 -γ缺陷[IFN -γ(-/-)]）的RBHi T细胞（有或无B细胞）转移至T细胞受体（TCR）-β和δ链缺陷（TCR -/-）或SCID小鼠体内。
结果：在TCR -/-小鼠中，野生型RBHi T细胞的转移引发伴有严重结肠炎的消耗性疾病。相比之下，IFN -γ(-/-) RBHi T细胞导致严重的体重减轻和低白蛋白血症，但结肠无明显炎症。这些小鼠的小肠呈现绒毛萎缩、刷状缘酶减少、肠上皮细胞增殖降低以及杯状细胞数量增加。这些变化需要B细胞的存在，因为SCID受体需要同时转移B细胞以及IFN -γ(-/-) RBHi T细胞才能使回肠病变发生。用抗IL - 4单克隆抗体治疗IFN -γ(-/-) RBHi T细胞的TCR -/-受体，可消除消耗性疾病和绒毛萎缩。
结论：失调的Th2细胞在小肠上皮引起萎缩性改变和杯状细胞转化，并通过过量的白细胞介素 - 4和B细胞介导消耗性疾病。
Background & Aims: T helper (Th):1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4(+)CD45RB(Hi) (RBHi) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2-deficient (RAG(-/-)) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. Methods: RBHi T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-gamma-defective [IFN-gamma(-/-)]) with or without B cells were transferred to T cell receptor (TCR)-beta and delta-chain-defective (TCR-/-) or SCID mice. Results: Transfer of Wt RBHi T cells induced wasting disease with severe colitis in the TCR-/- mice. In contrast, IFN-gamma(-/-) RBHi T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-gamma(-/-) RBHi T cells for ileal lesions to develop. Treatment of TCR-/- recipients of IFN-gamma(-/-) RBHi T cells with anti-IL-4 mAb abrogated both the wasting disease and the villus atrophy. Conclusions: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells.