Pathogenic T helper 2 (T_H2) 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 T_H2 cell responses. We found that TSLP signaling in mouse CD4⁺ T cells initiated transcriptional changes associated with T_H2 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 T_H2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did T_H2 cells stimulated with IL-4 alone. TSLP-mediated T_H2 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 T_H2 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 T_H2 cells. In human CD4⁺ T cells, TSLP and IL-4 promoted the generation of T_H2 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 T_H2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.

产生增加量的细胞因子白介素5（IL-5）和IL-13的致病性T辅助2（T _H 2）细胞促进了包括哮喘在内的过敏性疾病。胸腺基质淋巴细胞生成素（TSLP）是上皮和先天免疫细胞分泌的一种细胞因子，可刺激这种病原性T _H 2细胞反应。我们发现，小鼠CD4 ⁺ T细胞中的TSLP信号启动了与T _H 2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，从而增加了产生IL-4，IL-5和IL-13的T细胞的频率。此外，TSLP和IL-4编程的T _H2个细胞具有致病性表型，比单独用IL-4刺激的T _H 2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T _H 2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时加剧了致病性T _H 2细胞反应。瞬时TSLP信号在记忆T _H 2细胞中稳定地编程了致病潜力。在人类CD4 ⁺T细胞，TSLP和IL-4促进了T _H 2细胞的产生，产生了更多的IL-5和IL-13。与健康对照相比，哮喘儿童在外周血中显示出此类T细胞反应的增强。我们的数据支持致病性T _H 2细胞分化的顺序细胞因子模型，并为人变态反应性疾病中TSLP信号的靶向治疗提供了机械基础。