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生理性和病理性 T 细胞自身反应在 1 型糖尿病中汇聚。

Physiological and pathogenic T cell autoreactivity converge in type 1 diabetes.

机构信息

Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany.

Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London, UK.

出版信息

Nat Commun. 2024 Oct 29;15(1):9204. doi: 10.1038/s41467-024-53255-9.

DOI:10.1038/s41467-024-53255-9
PMID:39472557
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11522472/
Abstract

Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes.

摘要

自身免疫性疾病是由自身抗原介导的适应性免疫激活引起的；有趣的是，健康供体中也存在针对自身抗原的 T 细胞。因此，有必要评估健康和疾病中这种自身反应性库的动态变化。在这里，我们在 1 型糖尿病 (T1D) 及其标志性自身抗原之一谷氨酸脱羧酶 65 (GAD65) 的背景下研究生理与病理性自身反应过程。使用单细胞基因表达谱分析和串联 T 细胞受体 (TCR) 测序，我们发现 GAD65 特异性真正幼稚细胞存在于健康和疾病中，GAD65 特异性效应和记忆反应在健康供体和患者中的比例相似。对表型和 TCR 库的更深入评估揭示了 GAD65 特异性 TCR 的不同特征，包括患者中来自健康供体的克隆型的克隆大小较低。因此，我们提出了一个模型，即在生命早期需要针对 GAD65 的生理性自身免疫，并且易感性个体中这些生理性自身免疫过程的改变会引发明显的 1 型糖尿病。

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