Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies

Background: Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4⁺ T cells in children with IgE-mediated food allergies. Methods: Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4⁺ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4⁺ T cell differentiation was assessed by treating stimulated naïve CD4⁺ T cells from healthy volunteers with tacrolimus for 7 days. Results: Egg allergic infants had impaired development of IFNγ⁺ Th1 cells and FoxP3⁺ transitional CD4⁺ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4⁺ T cells from food allergic children after in vitro culture. SOCE of naïve CD4⁺ T cells was impaired in food allergic children. Naïve CD4⁺ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression. Conclusions: In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.