Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Sci Signal. 2018 Mar 13;11(521):eaam8858. doi: 10.1126/scisignal.aam8858.
Pathogenic T helper 2 (T2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic T2 cell responses. We found that TSLP signaling in mouse CD4 T cells initiated transcriptional changes associated with T2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13. Furthermore, the TSLP- and IL-4-programmed T2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did T2 cells stimulated with IL-4 alone. TSLP-mediated T2 cell induction involved distinct molecular pathways, including activation of the transcription factor STAT5 through the kinase JAK2 and repression of the transcription factor BCL6. Mice that received wild-type CD4 T cells had exacerbated pathogenic T2 cell responses upon exposure to house dust mites compared to mice that received TSLP receptor-deficient CD4 T cells. Transient TSLP signaling stably programmed pathogenic potential in memory T2 cells. In human CD4 T cells, TSLP and IL-4 promoted the generation of T2 cells that produced greater amounts of IL-5 and IL-13. Compared to healthy controls, asthmatic children showed enhancement of such T cell responses in peripheral blood. Our data support a sequential cytokine model for pathogenic T2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.
致病 T 辅助 2（T2）细胞产生大量白细胞介素-5（IL-5）和 IL-13，促进过敏疾病，包括哮喘。胸腺基质淋巴细胞生成素（TSLP），一种由上皮细胞和先天免疫细胞分泌的细胞因子，刺激这种致病 T2 细胞反应。我们发现，TSLP 信号在小鼠 CD4 T 细胞中启动了与 T2 细胞编程相关的转录变化。IL-4 信号放大并稳定了 T 细胞对 TSLP 的基因组反应，增加了产生 IL-4、IL-5 和 IL-13 的 T 细胞频率。此外，TSLP 和 IL-4 编程的 T2 细胞具有致病性表型，比单独用 IL-4 刺激的 T2 细胞产生更多的 IL-5 和 IL-13 和其他促炎细胞因子。TSLP 介导的 T2 细胞诱导涉及不同的分子途径，包括通过激酶 JAK2 激活转录因子 STAT5 和抑制转录因子 BCL6。与接受 TSLP 受体缺陷型 CD4 T 细胞的小鼠相比，接受野生型 CD4 T 细胞的小鼠在暴露于屋尘螨后，其致病性 T2 细胞反应加剧。TSLP 信号的短暂信号稳定地在记忆 T2 细胞中编程致病潜能。在人类 CD4 T 细胞中，TSLP 和 IL-4 促进了产生更多 IL-5 和 IL-13 的 T2 细胞的生成。与健康对照组相比，哮喘儿童在外周血中显示出这种 T 细胞反应的增强。我们的数据支持 T2 细胞分化的顺序细胞因子模型，并为靶向人类过敏疾病中 TSLP 信号提供了机制基础。
