Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naive CD8+T Cells in Type 1 Diabetic and Healthy Donors
Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naive CD8+T Cells in Type 1 Diabetic and Healthy Donors
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DOI：
10.1016/j.cmet.2018.07.007
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发表时间：
2018-12-04
期刊：
影响因子：
29
通讯作者：
Mallone, Roberto
中科院分区：
文献类型：
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作者：
Gonzalez-Duque, Sergio;Azoury, Marie Eliane;Mallone, Roberto
尽管 CD8(+) T 细胞介导的自身免疫性 β 细胞破坏发生在 1 型糖尿病 (T1D) 中，但 β 细胞处理和呈递的靶表位尚不清楚。为了识别它们，我们结合了肽组学和转录组学策略。炎症细胞因子增加体外肽呈递，同时上调人类白细胞抗原 (HLA) I 类表达。肽来源包含多种胰岛素颗粒蛋白和所有已知的 β 细胞抗原，但胰岛特异性葡萄糖 6 磷酸酶催化亚基相关蛋白除外。前胰岛素原产生先前描述的 HLA-A2 限制性表位。 Secretogranin V 及其 mRNA 剪接亚型 SCG5-009、proconvertase-2、urocortin-3、胰岛素基因增强蛋白 ISL-1 和胰岛淀粉样多肽转肽产物作为加工成 HLA-A2 限制性表位的抗原出现，如前所述，这些表位可被 T1D 和健康供体中循环的幼稚 CD8 (+) T 细胞识别，并且通过T1D 捐献者的胰腺浸润细胞。该肽组为了解 β 细胞的抗原加工以及开发 T 细胞生物标志物和耐受性疫苗接种策略开辟了新途径。
Although CD8(+) T-cell-mediated autoimmune beta cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by beta cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known beta cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8 (+) T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by beta cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.