In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response^1,2. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch^3,4,5,6,7. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell–IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset⁸, 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 γδ T cell–IL-3 signalling axis further acts by means of 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 on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases.

在幼稚的个体中，感觉神经元直接检测并响应过敏原，导致瘙痒感和局部先天免疫细胞的激活，从而启动过敏免疫反应^1,2。在慢性过敏性炎症的情况下，免疫因子激发感觉神经元，引起病理瘙痒^3,4,5,6,7。尽管这些双向神经免疫回路驱动对过敏原的反应，但免疫细胞是否调节初始状态下过敏原激活神经元的设定点尚不清楚。在这里，我们描述了一个 γδ T 细胞-IL-3 信号轴，它控制皮肤感觉神经元的过敏原反应性。我们定义了一种特征不佳的表皮 γδ T 细胞亚群⁸，称为 GD3 细胞，它产生其标志性的细胞因子 IL-3 以促进过敏性瘙痒和过敏性免疫反应的启动。从机制上讲，IL-3 以 JAK2 依赖性方式作用于表达 Il3ra 的感觉神经元，以降低它们过敏原激活的阈值，而不会独立引起瘙痒。该 γδ T 细胞-IL-3 信号轴通过 STAT5 进一步发挥作用，促进神经肽的产生和过敏免疫的启动。这些结果揭示了一种内源性免疫变阻器，它位于首次接触过敏原的上游并控制感觉神经元对过敏原的反应。该途径可以解释过敏易感性的个体差异，并为治疗过敏性疾病开辟新的治疗途径。