IgE-mediated food allergy and eosinophilic esophagitis (EoE) are diseases commonly triggered by milk. Milk-responsive CD4⁺ T cells producing type 2 cytokines are present in both diseases, yet the clinical manifestation of disease in milk allergy (MA) and EoE are distinct.

We sought to identify differences in CD4⁺ T cells between EoE and MA that may be responsible for distinct disease manifestations.

The total and milk-specific CD4⁺ T-cell phenotype of children with MA, children with EoE (active or in remission), and controls was measured using spectral flow cytometry of peripheral blood (all groups) or esophageal biopsies (EoE and control).

Circulating milk-responsive T cells could be identified in active EoE and MA. An increased frequency of T_H2A cells was also noted in MA and EoE. In circulating T cells, type 2 cytokine production was elevated in MA, but not EoE. Within the milk-responsive T follicular helper (T_FH) subset, a dichotomy of phenotype was noted: T_FH13 cells predominated in MA, while IL-10–producing T_FH cells predominated in EoE. In the esophagus, CD4⁺ T cells were constitutively activated and expressed not only type 2 cytokines, but also IL-10 and IL-21 in active EoE. IgG4 was produced from CD38⁺ plasma cells in close proximity to CD4⁺ T cells. In vitro activation studies demonstrated that IL-10 and IL-21 elicited strong IgG4 responses in B lymphocytes, while IL-4 and IL-13 promoted IgE production.

Our studies demonstrate a dichotomy of T_FH responses that may be the basis for different clinical manifestations to milk in EoE and MA.