Differential Tfh cell phenotypes distinguish IgE-mediated milk allergy from eosinophilic esophagitis in children.

Background: 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.

Objective: To identify CD4⁺ T cell differences between EoE and MA that may be responsible for distinct disease manifestations.

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

Results: Circulating milk-responsive T cells could be identified in active (A)-EoE and MA. An increased frequency of Th2A 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 Tfh subset, a dichotomy of phenotype was noted: Tfh13 cells predominated in MA, while IL-10-producing Tfh 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 A-EoE. There was production of IgG4 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.

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