Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5010-5. doi: 10.1073/pnas.1114931109. Epub 2012 Mar 7.
Adequate activation of CD4(+) T lymphocytes is essential for host defense against invading pathogens; however, exaggerated activity of effector CD4(+) T cells induces tissue damage, leading to inflammatory disorders such as inflammatory bowel diseases. Several unique subsets of intestinal innate immune cells have been identified. However, the direct involvement of innate immune cell subsets in the suppression of T-cell-dependent intestinal inflammation is poorly understood. Here, we report that intestinal CX(3)C chemokine receptor 1(high) (CX(3)CR1(high)) CD11b(+) CD11c(+) cells are responsible for prevention of intestinal inflammation through inhibition of T-cell responses. These cells inhibit CD4(+) T-cell proliferation in a cell contact-dependent manner and prevent T-cell-dependent colitis. The suppressive activity is abrogated in the absence of the IL-10/Stat3 pathway. These cells inhibit T-cell proliferation by two steps. Initially, CX(3)CR1(high) CD11b(+) CD11c(+) cells preferentially interact with T cells through highly expressed intercellular adhesion molecule-1/vascular cell adhesion molecule-1; then, they fail to activate T cells because of defective expression of CD80/CD86. The IL-10/Stat3 pathway mediates the reduction of CD80/CD86 expression. Transfer of wild-type CX(3)CR1(high) CD11b(+) CD11c(+) cells prevents development of colitis in myeloid-specific Stat3-deficient mice. Thus, these cells are regulatory myeloid cells that are responsible for maintaining intestinal homeostasis.
CD4(+) T 淋巴细胞的充分激活对于宿主抵御入侵病原体至关重要；然而，效应 CD4(+) T 细胞的过度活性会引起组织损伤，导致炎症性疾病，如炎症性肠病。已经鉴定出几种独特的肠道固有免疫细胞亚群。然而，固有免疫细胞亚群在抑制 T 细胞依赖性肠道炎症中的直接参与仍知之甚少。在这里，我们报告肠道 CX(3)C 趋化因子受体 1(高) (CX(3)CR1(高)) CD11b(+) CD11c(+)细胞通过抑制 T 细胞反应来预防肠道炎症。这些细胞以细胞接触依赖性方式抑制 CD4(+) T 细胞增殖，并防止 T 细胞依赖性结肠炎。在缺乏 IL-10/Stat3 途径的情况下，抑制活性被废除。这些细胞通过两步抑制 T 细胞增殖。最初，CX(3)CR1(高) CD11b(+) CD11c(+)细胞通过高表达细胞间黏附分子-1/血管细胞黏附分子-1与 T 细胞优先相互作用；然后，由于 CD80/CD86 的表达缺陷，它们无法激活 T 细胞。IL-10/Stat3 途径介导 CD80/CD86 表达的减少。野生型 CX(3)CR1(高) CD11b(+) CD11c(+)细胞的转移可防止髓样特异性 Stat3 缺陷型小鼠发生结肠炎。因此，这些细胞是负责维持肠道内稳态的调节性髓样细胞。
