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

• 成果类型: Article
• 署名作者: Flayer, Cameron H.; Kernin, Isabela J.; Matatia, Peri R.; Zeng, Xiangsunze; Yarmolinsky, David A.; Han, Cai; Naik, Parth R.; Buttaci, Dean R.; Aderhold, Pamela A.; Camire, Ryan B.; Zhu, Xueping; Tirard, Alice J.; McGuire, John T.; Smith, Neal P.; McKimmie, Clive S.; McAlpine, Cameron S.; Swirski, Filip K.; Woolf, Clifford J.; Villani, Alexandra-Chloe; Sokol, Caroline L.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; University of York - UK; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3913
• DOI: 10.1038/s41586-024-07869-0
• 发表日期: 2024-10-10
• 关键词: single-cell; dry skin; homeostasis; itch; activation; DEFENSE; pain

摘要

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 response1,2. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch3-7. 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 gamma delta T cell-IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal gamma delta 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 gamma delta 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. A gamma delta T cell-IL-3 signalling axis is defined that controls the allergen responsiveness of cutaneous sensory neurons, leading to evidence for an immune rheostat that governs sensory neuronal responses to allergens on first exposure.