Erin Janssen, Mrinmoy Das, Jordan Butts, Mohammed Alasharee, Saikat Mukherjee, Gabriel L. Lozano, Chitong Rao, Andrew F. Livingston, Brian Woods, Emma Smith, Zachary Peters, Elena Milin, Maria A. Beamer, Hazel Wilkie, Juan-Manuel Leyva-Castillo, Christy Kam, Ali Sobh, Majed Dasouki, Rima Hanna Wakim, Ghassan Dbaibo, Raif S. Geha
{"title":"T细胞中的DOCK8促进Th17和Treg细胞功能抑制粘膜肥大细胞并限制对口腔过敏反应的易感性","authors":"Erin Janssen, Mrinmoy Das, Jordan Butts, Mohammed Alasharee, Saikat Mukherjee, Gabriel L. Lozano, Chitong Rao, Andrew F. Livingston, Brian Woods, Emma Smith, Zachary Peters, Elena Milin, Maria A. Beamer, Hazel Wilkie, Juan-Manuel Leyva-Castillo, Christy Kam, Ali Sobh, Majed Dasouki, Rima Hanna Wakim, Ghassan Dbaibo, Raif S. Geha","doi":"10.1016/j.immuni.2025.06.004","DOIUrl":null,"url":null,"abstract":"Immunoglobulin E (IgE)-mediated release of mediators from mast cells (MCs) drives food allergy, and intestinal MC load is an important determinant of disease severity. Dedicator of cytokinesis 8 (DOCK8)-deficient patients are highly susceptible to food allergy. We found that they exhibited elevated serum MC tryptase levels, suggesting increased MC load. <em>Dock8</em><sup>−/−</sup> mice also had exaggerated IgE-mediated oral anaphylaxis, expansion of jejunal mucosal MCs (MMCs), and elevated serum levels of MMC-derived tryptase. This resulted in increased intestinal permeability, which promoted antigen absorption and thereby oral anaphylaxis. Mechanistically, these events were driven by an intestinal cascade in which reduced interleukin (IL)-17 cytokines led to dysbiosis, which drove IL-25 production. Increased IL-25 enhanced T helper (Th)2 production of IL-4 that expanded MMCs and exaggerated oral anaphylaxis. Furthermore, the failure of DOCK8-deficient T regulatory (Treg) cells to suppress intestinal IL-4 production and MC expansion left the exaggerated anaphylaxis unrestrained. These results suggest multi-faceted coordination between the microbiome, mucosal T cells, and MCs to restrict oral anaphylaxis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"37 1","pages":""},"PeriodicalIF":25.5000,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DOCK8 in T cells promotes Th17 and Treg cell functionality to restrain mucosal mast cells and limit susceptibility to oral anaphylaxis\",\"authors\":\"Erin Janssen, Mrinmoy Das, Jordan Butts, Mohammed Alasharee, Saikat Mukherjee, Gabriel L. Lozano, Chitong Rao, Andrew F. Livingston, Brian Woods, Emma Smith, Zachary Peters, Elena Milin, Maria A. Beamer, Hazel Wilkie, Juan-Manuel Leyva-Castillo, Christy Kam, Ali Sobh, Majed Dasouki, Rima Hanna Wakim, Ghassan Dbaibo, Raif S. Geha\",\"doi\":\"10.1016/j.immuni.2025.06.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Immunoglobulin E (IgE)-mediated release of mediators from mast cells (MCs) drives food allergy, and intestinal MC load is an important determinant of disease severity. Dedicator of cytokinesis 8 (DOCK8)-deficient patients are highly susceptible to food allergy. We found that they exhibited elevated serum MC tryptase levels, suggesting increased MC load. <em>Dock8</em><sup>−/−</sup> mice also had exaggerated IgE-mediated oral anaphylaxis, expansion of jejunal mucosal MCs (MMCs), and elevated serum levels of MMC-derived tryptase. This resulted in increased intestinal permeability, which promoted antigen absorption and thereby oral anaphylaxis. Mechanistically, these events were driven by an intestinal cascade in which reduced interleukin (IL)-17 cytokines led to dysbiosis, which drove IL-25 production. Increased IL-25 enhanced T helper (Th)2 production of IL-4 that expanded MMCs and exaggerated oral anaphylaxis. Furthermore, the failure of DOCK8-deficient T regulatory (Treg) cells to suppress intestinal IL-4 production and MC expansion left the exaggerated anaphylaxis unrestrained. These results suggest multi-faceted coordination between the microbiome, mucosal T cells, and MCs to restrict oral anaphylaxis.\",\"PeriodicalId\":13269,\"journal\":{\"name\":\"Immunity\",\"volume\":\"37 1\",\"pages\":\"\"},\"PeriodicalIF\":25.5000,\"publicationDate\":\"2025-06-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.immuni.2025.06.004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2025.06.004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
DOCK8 in T cells promotes Th17 and Treg cell functionality to restrain mucosal mast cells and limit susceptibility to oral anaphylaxis
Immunoglobulin E (IgE)-mediated release of mediators from mast cells (MCs) drives food allergy, and intestinal MC load is an important determinant of disease severity. Dedicator of cytokinesis 8 (DOCK8)-deficient patients are highly susceptible to food allergy. We found that they exhibited elevated serum MC tryptase levels, suggesting increased MC load. Dock8−/− mice also had exaggerated IgE-mediated oral anaphylaxis, expansion of jejunal mucosal MCs (MMCs), and elevated serum levels of MMC-derived tryptase. This resulted in increased intestinal permeability, which promoted antigen absorption and thereby oral anaphylaxis. Mechanistically, these events were driven by an intestinal cascade in which reduced interleukin (IL)-17 cytokines led to dysbiosis, which drove IL-25 production. Increased IL-25 enhanced T helper (Th)2 production of IL-4 that expanded MMCs and exaggerated oral anaphylaxis. Furthermore, the failure of DOCK8-deficient T regulatory (Treg) cells to suppress intestinal IL-4 production and MC expansion left the exaggerated anaphylaxis unrestrained. These results suggest multi-faceted coordination between the microbiome, mucosal T cells, and MCs to restrict oral anaphylaxis.
期刊介绍:
Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.