Autophagy in thymic epithelium and T cell tolerance

胸腺上皮自噬和 T 细胞耐受

• 批准号: 116141321
• 负责人: Professor Dr. Ludger Klein
• 金额: --
• 依托单位: Forschungsbereich Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/116141321?language=en
• 关键词: Autophagy; thymic; epithelium; cell; tolerance

Thymic epithelial cells (TEC) are the only non-hematopoietic cells that constitutively express high levels of MHC class II (MHC II). The recognition of MHC II bound peptides on TEC by developing thymocytes ensures (i) the generation of a functional, i.e. self-MHC restricted, CD4 T cell repertoire, and (ii) the removal (negative selection) or functional deviation (regulatory T cell induction) of autoreactive CD4 T cells. MHC II / peptide ligands are primarily generated through processing of exogenous proteins. TEC, however, exhibit a remarkable inefficiency in capturing and processing extracellular antigens, suggesting alternative pathways of MHC II loading. Cell culture models have indicated that autophagy, a bulk protein degradation process up-regulated upon starvation to sustain metabolic fitness, may shuttle intracellular material into the MHC II pathway. We could recently show that interference with autophagy specifically in TEC led to altered selection of certain MHC II-restricted T cell specificities and resulted in severe colitis and multi-organ inflammation. Our findings suggest that autophagy contributes to T cell selection by focusing the MHC II / peptide repertoire of TEC on their intracellular milieu, which notably comprises a wide array of otherwise “peripheral” self-antigens. Here, we propose to test this hypothesis using two novel transgenic model systems and to address mechanistic aspects of the failure of tolerance that is caused by the absence of autophagy in TEC. Furthermore, we plan to explore the regulation of autophagy in TEC.

胸腺上皮细胞（TEC）是唯一组成性表达高水平MHC II类（MHC II）的非造血细胞。发育中的胸腺细胞对TEC上MHC II结合肽的识别确保了(i)产生功能性的，即自身MHC受限的CD4 T细胞库，以及（II）去除（负选择）或功能偏差（调节性T细胞诱导）自身反应性CD4 T细胞。MHC II /肽配体主要通过外源蛋白加工产生。然而，TEC在捕获和处理细胞外抗原方面表现出显著的低效率，这表明MHC II装载的其他途径。细胞培养模型表明，自噬（一种在饥饿状态下被上调以维持代谢适应性的大量蛋白质降解过程）可能将细胞内物质运送到MHC II途径。我们最近可以证明，对TEC中自噬的干扰导致某些MHC ii限制性T细胞特异性的选择改变，并导致严重的结肠炎和多器官炎症。我们的研究结果表明，自噬通过将TEC的MHC II /肽库聚焦于细胞内环境，从而有助于T细胞的选择，细胞内环境主要包括一系列其他“外周”自身抗原。在这里，我们建议使用两种新的转基因模型系统来验证这一假设，并解决由TEC中缺乏自噬引起的耐受性失败的机制方面的问题。此外，我们计划探讨自噬在TEC中的调控作用。