Loss of tolerance in cow milk allergic endotypes is linked to allergen-specific CD4+ T cell subset outgrowth and microbial dysbioses

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 and differential gene expression analysis approach, we characterized the CD4+ T cell subsets associated with both IgE and non-IgE mediated CMA endotypes and assessed their associations with gut bacterial compositions. Analysis of conventional (Tcon) and regulatory (Treg) CD4+ T cells revealed an expansion of inflammatory Tcon in CMA subjects, coincident with TH-like subset polarization and alterations in Treg signaling pathways. TH2-skewing was dominant in IgE mediated allergies, whereas subjects with non-IgE mediated allergies exhibited a CD4+ T cell compartment dominated by a novel TH response. Microbial dysbiosis was observed across all CMA endotypes, 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 endotypes.