Ulcerative colitis and autoirnmunity induced by loss of myeloid αv integrins
Ulcerative colitis and autoirnmunity induced by loss of myeloid αv integrins
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DOI：
10.1073/pnas.0707421104
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发表时间：
2007-10-02
影响因子：
11.1
通讯作者：
Hynes, Richard O.
中科院分区：
文献类型：
--
作者：
Lacy-Hulbert, Adam;Smith, Aileen M.;Hynes, Richard O.
胃肠道不断受到外来抗原和共生菌的挑战，但仍能保持免疫静止状态。最近的进展强调了调节性淋巴细胞和免疫抑制细胞因子在控制粘膜免疫中的积极抑制的重要性。这些机制的失败导致了炎症性肠病的发展，但这些调控网络是如何建立的仍不清楚。在这里，我们展示了αv整合素在调节粘膜免疫中的关键作用。我们报告免疫系统中av基因的缺失会导致严重的结肠炎、自身免疫性疾病和癌症。缺乏免疫细胞av的小鼠结肠中的调节性T(Treg)细胞较少，激活的T细胞和T细胞细胞因子的产生相应增加，从而导致结肠炎。利用条件性基因打靶，我们证明了这是由于髓系细胞中av的丢失所致。此外，我们发现肠道相关的巨噬细胞和树突状细胞都不能有效地去除凋亡细胞和诱导Treg细胞。我们的结果确定了髓系av整合素在产生粘膜Treg细胞中的重要作用，并强调了抗原提呈细胞在建立免疫耐受中的重要性。
The gastrointestinal tract is constantly challenged by foreign antigens and commensal bacteria but nonetheless is able to maintain a state of immunological quiescence. Recent advances have highlighted the importance of active suppression by regulatory lymphocytes and immunosuppressive cytokines in controlling mucosal immunity. Failures of these mechanisms contribute to the development of inflammatory bowel disease, but how these regulatory networks are established remains unclear. Here, we demonstrate key roles for alpha v integrins in regulation of mucosal immunity. We report that deletion of av in the immune system causes severe colitis, autoimmunity, and cancer. Mice lacking immune cell av have fewer regulatory T (Treg) cells in the colon and corresponding increases in activated T cells and T cell cytokine production, leading to colitis. Using conditional gene targeting, we demonstrate that this is specifically attributable to loss of av from myeloid cells. Furthermore, we show that gut-associated macrophages and dendritic cells fail both to remove apoptotic cells efficiently and to induce Treg cells. Our results identify a vital role for myeloid av integrins in generating mucosal Treg cells and emphasize the importance of antigen-presenting cells in establishing immune tolerance.