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

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CD4+ T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes
Immunity ( IF 25.5 ) Pub Date : 2024-08-29 , DOI: 10.1016/j.immuni.2024.07.024
Jason S Mitchell ₁ , Justin A Spanier ₂ , Alexander J Dwyer ₃ , Todd P Knutson ₄ , Mohannad H Alkhatib ₃ , Gina Qian ₃ , Matthew E Weno ₃ , Yixin Chen ₃ , Zachary R Shaheen ₅ , Christopher G Tucker ₃ , Takashi O Kangas ₃ , Milagros Silva Morales ₃ , Nubia Silva ₆ , Tsuneyasu Kaisho ₇ , Michael A Farrar ₈ , Brian T Fife ₂

Affiliation

Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA; Center for Autoimmune Disease Research, University of Minnesota, Minneapolis, MN, USA.
Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA.
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, Division of Pediatric Rheumatology, Allergy, & Immunology, University of Minnesota, Minneapolis, MN, USA.
Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA.
Department of Immunology Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.

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.

中文翻译：

与胰岛素-嗜铬粒蛋白 A 的杂交肽反应的 CD4+ T 细胞具有不同的效应命运，在自身免疫性糖尿病中具有致病性

T 细胞介导的胰岛破坏是自身免疫性糖尿病的标志。在这里，我们检查了非肥胖糖尿病（NOD）小鼠糖尿病启动期间 CD4 + T 细胞对四种不同胰岛素衍生表位的反应的动力学和致病性。来自胰腺的四聚体分选的 CD4+ T 细胞的单细胞 RNA 测序显示，胰岛抗原特异性 T 细胞采用多种命运，并且需要 XCR1+ 树突状细胞来激活。杂交胰岛素 C-嗜铬粒蛋白 A （InsC-ChgA）特异性 CD4+ T 细胞偏向于不同的辅助性 T 型 1 （Th1）效应表型，而大多数胰岛素 B 链和杂交胰岛素 C 胰岛淀粉样蛋白多肽特异性 CD4+ T 细胞分别表现出调节表型和早期或弱 Th1 表型。InsC-ChgA 特异性 CD4 + T 细胞在转移时具有独特的致病性，抗 InsC-ChgA：IAg7 抗体可预防自发性糖尿病。我们的研究结果强调了糖尿病中 T 细胞对胰岛素衍生表位反应的异质性，并论证了抗原特异性疗法的可行性，该疗法可以减弱引起自身免疫的致病性 CD4+ T 细胞的反应。

更新日期：2024-08-29

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