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

Abstract 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.