Cattin-Roy Alexis N, Laffey Kimberly G, Le Luan B, Schrum Adam G, Zaghouani Habib
Department of Molecular Microbiology & Immunology.
Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA.
J Clin Invest. 2024 Dec 2;134(23):e163417. doi: 10.1172/JCI163417.
Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.
尽管胸腺中存在功能性抗原呈递机制和可察觉的中枢耐受过程，但1型糖尿病（T1D）仍会自发发展。我们发现，胸腺内用白细胞介素-4（IL-4）进行富集可微调早期胸腺祖细胞（ETP）中通过IL-4/白细胞介素-13异源受体（HR）的信号传导，增强对自身反应性T细胞的阴性选择，维持一个缺乏表达疾病相关T细胞受体（TCR）基因克隆的多样化T细胞库，并保护非肥胖糖尿病（NOD）小鼠免于患T1D。事实上，最佳的IL-4会激活信号转导和转录激活因子（STAT）转录因子，将ETP的命运决定编程为向在阴性T细胞选择和致糖尿病T细胞克隆清除中敏捷的CD11c + CD8α + 树突状细胞（DC）发展。然而，由于NOD胸腺中不变自然杀伤T（iNKT）2细胞频率降低，IL-4处于次优水平，调节STAT激活以将ETP的命运决定编程为向T细胞谱系发展，导致阴性选择减少、TCR库克隆受限以及自发性T1D的表现。这些见解揭示了IL-4影响T1D的另一种相互作用。
