Division of Allergy and Immunology,Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
Division of Human Genetics, Department of Pediatrics Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
Sci Signal. 2023 Sep 12;16(802):eadg6360. doi: 10.1126/scisignal.adg6360.
The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4 T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in . We showed that about 10% of esophageal-derived memory CD4 T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4 T cells were present in the circulation of individuals with EoE. TSLP increased the proliferation of CD4 T cells, enhanced type 2 cytokine production, induced the increased abundance of its own receptor, and modified the expression of 212 genes. The epigenetic response to TSLP was associated with an enrichment in BATF and IRF4 chromatin-binding sites, and these transcription factors were induced by TSLP, providing a feed-forward loop. The numbers of circulating and esophageal CD4 T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4 T cells. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE.
细胞因子胸腺基质淋巴细胞生成素 (TSLP) 介导 2 型免疫反应，干扰 TSLP 活性的治疗方法已用于哮喘的临床治疗。在这里，我们研究了 TSLP 是否通过直接刺激人类 CD4 T 细胞来促进过敏炎症，以及这个过程是否在嗜酸性食管炎 (EoE) 中起作用，EoE 是一种与 变体相关的疾病。我们发现，来自 EoE 个体的食管来源的记忆 CD4 T 细胞中约有 10%，而来自对照个体的细胞中不到 3%，表达 TSLP 的受体，并通过测量转录因子 STAT5 的磷酸化直接对 TSLP 作出反应，STAT5 是 TSLP 刺激下游激活的转录因子。因此，在 EoE 个体的循环中存在数量增加的 TSLP 反应性记忆 CD4 T 细胞。TSLP 增加 CD4 T 细胞的增殖，增强 2 型细胞因子的产生，诱导其自身受体的丰度增加，并改变 212 个基因的表达。对 TSLP 的表观遗传反应与 BATF 和 IRF4 染色质结合位点的富集相关，并且这些转录因子被 TSLP 诱导，提供了一个正反馈回路。对 TSLP 有反应的循环和食管 CD4 T 细胞的数量与食管嗜酸性粒细胞的数量相关，支持 TSLP 在驱动 EoE 发病机制中的潜在功能作用，并为基于循环 CD4 T 细胞中 TSLP 诱导的 STAT5 磷酸化程度的基于血液的诊断测试提供了依据。这些发现突出了 TSLP 抑制剂在治疗 EoE 中的潜在治疗价值。
