An important regulatory role for CD4+CD8αα T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease
An important regulatory role for CD4+CD8αα T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease
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DOI：
10.1073/pnas.0831037100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Ray, A
中科院分区：
文献类型：
--
作者：
Das, G;Augustine, MM;Ray, A
尽管不断受到环境抗原的刺激，维持肠粘膜内动态平衡的正常免疫调节机制在炎症性肠病中受到破坏。尽管先前的研究表明，肠道上皮内淋巴细胞可预防自发性肠道炎症，但对肠道上皮内淋巴细胞群体中调节细胞的特征了解有限。在这里，我们发现肠上皮内淋巴细胞群中存在的CD4(+)CD8α(+)双阳性细胞可以通过IL-10依赖的方式抑制T辅助细胞1诱导的肠道炎症。当转移到RAG-1-/-小鼠体内时，沿着Th2而不是Th1谱系刺激的CD4(+)T细胞在到达肠道上皮细胞时获得CD8α表达，并在到达那里时增强其IL-10的产生。我们发现，在小鼠肠道微环境中，前体CD4+T细胞在受到IL-4的有限但不重复的刺激后，能够成为双阳性调节细胞。CD8aa的获得和IL-10的产生都严重依赖于核因子-kappaB-GATA-3轴，我们之前已经证明，这是分化为Th2表型和诱导呼吸道炎症所必需的。我们的研究确定了一种在肠道中产生调节性T细胞的机制，该机制可能在控制炎症性肠病中发挥重要作用。
The normal immunoregulatory mechanisms that maintain homeostasis in the intestinal mucosa, despite continuous provocation by environmental antigens, are jeopardized in inflammatory bowel diseases. Although previous studies have suggested that intestinal intraepithelial lymphocytes prevent spontaneous intestinal inflammation, there is limited knowledge about the characteristics of regulatory cells in the intestinal intraepithelial lymphocytes population. Here we show that CD4(+)CD8alphaalpha(+) double-positive cells present in the intestinal intraepithelial lymphocytes population can suppress T helper 1-induced intestinal inflammation in an IL-10-dependent fashion. CD4(+) T cells stimulated along the Th2 but not the Th1 lineage, when transferred to RAG-1-/- mice, acquire CD8alphaalpha expression on reaching the intestinal epithelium, and on arrival there, augment their production of IL-10. We show that a precursor CD4+ T cell after limited, but not repeated, stimulation by IL-4 is able to become a double-positive-regulatory cell on exposure to the intestinal microenvironment in mice. Both CD8aa acquisition and IL-10 production depend critically on the NF-kappaB-GATA-3-axis that we have previously shown is essential for differentiation to the Th2 phenotype and for the induction of airway inflammation. Our studies identify a mechanism for the generation of regulatory T cells in the intestine that may play an important role in controlling inflammatory bowel disease.