Department of Biomedical Research, National Jewish Health, Denver, CO.
Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO.
J Exp Med. 2021 Feb 1;218(2). doi: 10.1084/jem.20192135.
The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.
几十年来，鉴定主要组织相容性复合体 II (MHCII) 分子呈递的肽表位，从而驱动自身免疫性疾病的 CD4 T 细胞成分，一直是一个艰巨的挑战。在 1 型糖尿病 (T1D) 中，最近对这一问题的深入了解来自于这样一个认识，即几个重要的表位不是直接从蛋白质来源加工而来，而是通过融合分泌颗粒蛋白的不同肽片段来创建新的嵌合表位。我们提出，这种融合是通过一种称为转肽反应的逆向蛋白水解反应来完成的，该反应发生在胰腺蛋白的分解代谢周转期间，此时分泌颗粒与溶酶体融合（胞噬作用）。在这里，我们证明了几个高度抗原性的致糖尿病 CD4 T 细胞嵌合表位，这些表位是通过用溶酶体蛋白酶组织蛋白酶 L (Cat-L) 消化颗粒蛋白的适当无活性片段产生的。该途径对于如何在外周打破 T1D 和其他自身免疫性疾病中的自身耐受性具有重要意义。
