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.