Allergen-specific CD4+ T cell dysfunction drives loss of tolerance and distinct immunopathological changes in cow milk allergy subtypes

Cow milk allergy (CMA) is the most prevalent pediatric food allergy, presenting in IgE- and non-IgE mediated forms. Currently, the CD4+ T-cell inflammatory responses underlying non-IgE CMA remain poorly characterized. By applying an allergen-reactive CD4+ T cell sorting approach and differential gene expression analysis, we characterized the T-helper (Th) subsets associated with CMA phenotypes and assessed associations of with the fecal microbiome. Analysis of conventional (Tcon) and regulatory (Treg) CD4+ T cells revealed an outgrowth of inflammatory Tcon in CMA subjects, coincident with decreases in Treg signaling pathways. Th2 skewing characterized IgE-mediated disease, whereas non-IgE mediated subjects exhibited a CD4+ T cell compartment dominated by a novel Th response. Microbial dysbiosis was observed across CMA phenotypes, and network mapping revealed significant associations between a decrease in butyrate producing bacteria and the presence of inflammatory Th-like subsets. These insights link the composition of the allergen-reactive Tcon/Treg compartment to CMA pathology and identifies differences in bacterial dysbioses associated with specific disease phenotypes.

牛乳过敏（Cow milk allergy, CMA）是最常见的儿科食物过敏，可分为免疫球蛋白E（IgE）介导型与非IgE介导型两种发病机制。目前，非IgE介导型CMA背后的CD4+ T细胞炎症反应机制仍未得到充分阐明。本研究通过过敏原反应性CD4+ T细胞分选技术与差异基因表达分析，对与CMA表型相关的辅助性T细胞（T-helper, Th）亚群进行了表征，并评估了其与粪便微生物组的关联。对常规CD4+ T细胞（conventional T cell, Tcon）与调节性CD4+ T细胞（regulatory T cell, Treg）的分析显示，CMA受试者体内炎性Tcon出现扩增，同时伴随Treg信号通路的活性下调。Th2极化是IgE介导型CMA的特征，而非IgE介导型受试者的CD4+ T细胞区室则以一种新型Th细胞应答为主要特征。所有CMA表型均存在微生物群落失调，且网络映射分析显示，产丁酸菌丰度降低与炎性Th样亚群的存在存在显著关联。上述研究结果将过敏原反应性Tcon/Treg区室的组成与CMA的病理机制联系起来，并明确了与不同疾病表型相关的微生物群落失调差异。