Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Center for Systems Immunology, Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Immunol. 2024 Nov;25(11):2124-2139. doi: 10.1038/s41590-024-01986-8. Epub 2024 Oct 11.
The mechanisms that guide T helper 2 (T2) cell differentiation in barrier tissues are unclear. Here we describe the molecular pathways driving allergen-specific T2 cells using temporal, spatial and single-cell transcriptomic tracking of house dust mite-specific T cells in mice. Differentiation and migration of lung allergen-specific T2 cells requires early expression of the transcriptional repressor Blimp-1. Loss of Blimp-1 during priming in the lymph node ablated the formation of T2 cells in the lung, indicating early Blimp-1 promotes T2 cells with migratory capability. IL-2/STAT5 signals and autocrine/paracrine IL-10 from house dust mite-specific T cells were essential for Blimp-1 and subsequent GATA3 upregulation through repression of Bcl6 and Bach2. Spatial microniches of IL-2 in the lymph node supported the earliest Blimp-1T2 cells, demonstrating lymph node localization is a driver of T2 initiation. Our findings identify an early requirement for IL-2-mediated spatial microniches that integrate with allergen-driven IL-10 from responding T cells to drive allergic asthma.
指导 2 型辅助性 T 细胞（T2）在屏障组织中分化的机制尚不清楚。在这里，我们使用尘螨特异性 T 细胞在小鼠中的时间、空间和单细胞转录组跟踪，描述了驱动过敏原特异性 T2 细胞的分子途径。肺过敏原特异性 T2 细胞的分化和迁移需要转录抑制因子 Blimp-1 的早期表达。在淋巴结中的初始阶段缺失 Blimp-1 会消除肺中 T2 细胞的形成，表明早期 Blimp-1 促进具有迁移能力的 T2 细胞。IL-2/STAT5 信号和尘螨特异性 T 细胞的自分泌/旁分泌 IL-10 对于 Blimp-1 和随后的 GATA3 上调是必需的，这是通过抑制 Bcl6 和 Bach2 实现的。淋巴结中 IL-2 的空间微环境对于最早的 Blimp-1T2 细胞是必需的，这表明淋巴结定位是 T2 起始的驱动因素。我们的发现确定了早期需要 IL-2 介导的空间微环境，该微环境与反应性 T 细胞驱动的过敏原诱导的 IL-10 相结合，从而引发过敏性哮喘。
