Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045.
Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO 80045.
Proc Natl Acad Sci U S A. 2021 Oct 12;118(41). doi: 10.1073/pnas.2107208118.
Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.
细胞毒性 CD8 T 淋巴细胞在许多自身免疫性疾病的组织破坏中发挥核心作用。在 1 型糖尿病 (T1D) 中，胰岛素及其前体胰岛素原是 T 细胞靶向的主要自身抗原。我们全面检查了来自有和没有 T1D 的器官供体胰岛中获得的 CD8 T 细胞对胰岛素原的特异性，并鉴定了整个胰岛素原蛋白和源自胰岛素原信使 RNA 的核糖体产物缺陷的表位。与非糖尿病供体相比，T1D 供体中胰岛素原反应性 T 细胞的频率明显更高，并且个体 T1D 供体之间也存在差异，范围从 3%到 40%以上，HLA-A*02:01 阳性的 T1D 器官供体中频率更高。只有对从 T1D 供体中分离出的与胰岛素原相关肽反应的 T 细胞表现出强烈的自身反应性。在另一组新诊断的 T1D 患者的外周血中也观察到了对胰岛素原相似区域的反应性。这些发现对设计抗原特异性免疫疗法和识别可能从这些干预中受益的个体具有重要意义。
