A γδ T cell–IL-3 axis controls allergic responses through sensory neurons

Abstract

In naïve individuals, sensory neurons directly detect and respond to allergens, leading both to the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch. While these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naïve state is unknown. Here we describe a gd T cell-IL-3 signaling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal gd T cell subset, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This gd T cell-IL-3 signaling axis further acts via STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens upon first exposure. This pathway may explain individual differences in allergic susceptibility and opens novel therapeutic avenues for treating allergic diseases.