美国明尼苏达大学Brian T. Fife小组发现，对来自胰岛素-嗜铬颗粒A的杂交肽反应的CD4⁺ T细胞采取独特的效应命运并在自身免疫性糖尿病中具有致病性。2024年8月29日，国际知名学术期刊《免疫》在线发表了这一成果。

研究人员揭示了非肥胖糖尿病（NOD）小鼠糖尿病发病初期针对四种不同胰岛素衍生表位的CD4⁺ T细胞反应的动态及其致病性。对胰腺中四聚体分选的CD4⁺ T细胞进行的单细胞RNA测序显示，特异性识别胰岛抗原的T细胞采用了多种命运，并且需要XCR1⁺树突状细胞的激活。

特异性识别胰岛素C-嗜铬颗粒A（InsC-ChgA）杂交肽的CD4⁺ T细胞倾向于独特的T辅助1型（Th1）效应表型，而大多数识别胰岛素B链和胰岛素C-胰岛淀粉样多肽杂交肽的CD4⁺ T细胞分别表现出调节性表型和早期或弱的Th1表型。InsC-ChgA特异性的CD4⁺ T细胞在转移后表现出独特的致病性，且抗InsC-ChgA抗体可预防自发性糖尿病。这些研究结果强调了糖尿病中针对胰岛素衍生表位的T细胞反应的异质性，并支持通过抗原特异性疗法来削弱致病性CD4⁺ T细胞引发的自身免疫反应的可行性。

据了解，T细胞介导的胰岛破坏是自身免疫性糖尿病的标志。

附：英文原文

Title: CD4+ T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes

Author: Jason S. Mitchell, Justin A. Spanier, Alexander J. Dwyer, Todd P. Knutson, Mohannad H. Alkhatib, Gina Qian, Matthew E. Weno, Yixin Chen, Zachary R. Shaheen, Christopher G. Tucker, Takashi O. Kangas, Milagros Silva Morales, Nubia Silva, Tsuneyasu Kaisho, Michael A. Farrar, Brian T. Fife

Issue&Volume: 2024-08-29

Abstract: T cell-mediated islet destruction is a hallmark of autoimmune diabetes. Here, we examined the dynamics and pathogenicity of CD4+ T cell responses to four different insulin-derived epitopes during diabetes initiation in non-obese diabetic (NOD) mice. Single-cell RNA sequencing of tetramer-sorted CD4+ T cells from the pancreas revealed that islet-antigen-specific T cells adopted a wide variety of fates and required XCR1+ dendritic cells for their activation. Hybrid-insulin C-chromogranin A (InsC-ChgA)-specific CD4+ T cells skewed toward a distinct T helper type 1 (Th1) effector phenotype, whereas the majority of insulin B chain and hybrid-insulin C-islet amyloid polypeptide-specific CD4+ T cells exhibited a regulatory phenotype and early or weak Th1 phenotype, respectively. InsC-ChgA-specific CD4+ T cells were uniquely pathogenic upon transfer, and an anti-InsC-ChgA:IAg7 antibody prevented spontaneous diabetes. Our findings highlight the heterogeneity of T cell responses to insulin-derived epitopes in diabetes and argue for the feasibility of antigen-specific therapies that blunts the response of pathogenic CD4+ T cells causing autoimmunity.

DOI: 10.1016/j.immuni.2024.07.024

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00373-X