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

Cameron H. Flayer, Isabela J. Kernin, Peri R. Matatia, Xiangsunze Zeng, David A. Yarmolinsky, Cai Han, Parth R. Naik, Dean R. Buttaci, Pamela A. Aderhold, Ryan B. Camire, Xueping Zhu, Alice J. Tirard, John T. McGuire, Neal P. Smith, Clive S. McKimmie, Cameron S. McAlpine, Filip K. Swirski, Clifford J. Woolf, Alexandra-Chloe Villani and Caroline L. Sokol ()
Additional contact information
Cameron H. Flayer: Harvard Medical School
Isabela J. Kernin: Harvard Medical School
Peri R. Matatia: Harvard Medical School
Xiangsunze Zeng: Harvard Medical School
David A. Yarmolinsky: Harvard Medical School
Cai Han: Harvard Medical School
Parth R. Naik: Harvard Medical School
Dean R. Buttaci: Harvard Medical School
Pamela A. Aderhold: Harvard Medical School
Ryan B. Camire: Harvard Medical School
Xueping Zhu: Harvard Medical School
Alice J. Tirard: Harvard Medical School
John T. McGuire: Harvard Medical School
Neal P. Smith: Harvard Medical School
Clive S. McKimmie: University of York
Cameron S. McAlpine: Icahn School of Medicine at Mount Sinai
Filip K. Swirski: Icahn School of Medicine at Mount Sinai
Clifford J. Woolf: Harvard Medical School
Alexandra-Chloe Villani: Harvard Medical School
Caroline L. Sokol: Harvard Medical School

Nature, 2024, vol. 634, issue 8033, 440-446

Abstract: Abstract 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 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.

Date: 2024
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DOI: 10.1038/s41586-024-07869-0

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