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 na & iuml;ve CD4(+) T cells in children with IgE-mediated food allergies.<br /> 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. Na & iuml;ve 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 na & iuml;ve CD4(+) T cells from healthy volunteers with tacrolimus for 7 days.<br /> Results Egg allergic infants had impaired development of IFN gamma(+) Th1 cells and FoxP3(+) transitional CD4(+) T cells compared with non-allergic infants. This parallels reduced T-bet, IFN gamma and FoxP3 expression in na & iuml;ve CD4(+) T cells from food allergic children after in vitro culture. SOCE of na & iuml;ve CD4(+) T cells was impaired in food allergic children. Na & iuml;ve CD4(+) T cells treated with tacrolimus had reduced IFN gamma, T-bet, and FoxP3, but preserved IL-4 expression.<br /> 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.