Sodium chloride is an ionic checkpoint for human Th2 cell responses and shapes the atopic skin microenvironment

There has been a strong increase in the incidence of allergic diseases over the last 50 years.Environmental factors most likely account for this phenomenon. However, the nature of thesefactors and the mode of action by which they induce the type 2 immune deviation, which ischaracteristic of atopic diseases, remains unclear. It has previously been reported that dietarysodium chloride promotes the polarization of Th17 cells with implications for autoimmunediseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potentlypromotes Th2 cell responses on multiple regulatory levels. Sodium chloride enhanced IL-4 andIL-13 production while suppressing IFN-gamma production in effector T cells. It diverted alternativeT cell fates into the Th2 cell phenotype and also induced de novo Th2 cell polarization fromnaïve T cell precursors. Mechanistically, it exerted its effects via the osmosensitivetranscription factor NFAT5 and the kinase SGK-1, which regulated Th2 signature cytokinesand master transcription factors in hyperosmolar salt conditions. The skin of patients sufferingfrom atopic dermatitis contained highly elevated amounts of sodium compared to non-lesionalatopic and healthy skin. This demonstrates that sodium chloride represents a so far overlookedcutaneous microenvironmental factor in atopic dermatitis that can induce Th2 cell responses,the orchestrators of allergic diseases. Together, our data propose ionic signaling throughsodium chloride as a novel checkpoint and potential therapeutic target for type 2 immunity andits associated allergic diseases.