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

Abstract

AbstractBackgroundReasons 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.MethodsPeripheral 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.ResultsEgg 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.ConclusionsIn 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.