Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice
Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice
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DOI：
10.1038/nature06110
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发表时间：
2007-09-20
期刊：
影响因子：
64.8
通讯作者：
Sheppard, Dean
中科院分区：
文献类型：
--
作者：
Travis, Mark A.;Reizis, Boris;Sheppard, Dean
细胞因子转化生长因子-β（TGF-β）是获得性免疫的重要负调节因子（1-3）。TGF-β是由细胞分泌的一种非活性前体，必须被激活才能发挥生物学作用（4），但调节免疫系统中TGF-β激活和功能的机制知之甚少。在这里，我们发现白细胞上的TGF-β激活整合素α（v）β（8）的条件性缺失会导致小鼠严重的炎症性肠病和年龄相关的自身免疫。这种自身免疫表型主要是由于树突细胞上缺乏α（v）β（8），因为主要在树突细胞上缺乏α（v）β（8）的小鼠与所有白细胞上缺乏α（v）β（8）的小鼠发展相同的免疫异常，而仅在T细胞上缺乏α（v）β（8）的小鼠在表型上是正常的。我们进一步表明，缺乏α（v）β（8）的树突状细胞在体外不能诱导调节性T细胞（T-R细胞），这种作用取决于TGF-β活性。此外，树突状细胞上缺乏alpha（v）beta（8）的小鼠结肠组织中T-R细胞的比例降低。这些结果表明，α（v）β（8）介导的树突状细胞的TGF-β活化对于预防导致炎性肠病和自身免疫的免疫功能障碍是必不可少的，这种作用至少部分是由于树突状细胞上的α（v）β（8）诱导和/或维持组织T-R细胞的能力。
The cytokine transforming growth factor-beta (TGF-beta) is an important negative regulator of adaptive immunity(1-3). TGF-beta is secreted by cells as an inactive precursor that must be activated to exert biological effects(4), but the mechanisms that regulate TGF-beta activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-beta-activating integrin alpha(v)beta(8) on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha(v)beta(8) on dendritic cells, as mice lacking alpha(v)beta(8) principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha(v)beta(8) on all leukocytes, whereas mice lacking alpha(v)beta(8) on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha(v)beta(8) fail to induce regulatory T cells (T-R cells) in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha(v)beta(8) on dendritic cells have reduced proportions of T-R cells in colonic tissue. These results suggest that alpha(v)beta(8)-mediated TGF-beta activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of alpha(v)beta(8) on dendritic cells to induce and/or maintain tissue T-R cells.