美国波士顿儿童医院和哈佛医学院Raif S. Geha团队的一项最新研究显示，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。2025年6月25日，国际知名学术期刊《免疫学》发表了这一成果。

该课题组人员发现他们表现出升高的血清MC胰蛋白酶水平，表明MC负荷增加。Dock8^-/-小鼠也有ige介导的口服过敏反应，空肠黏膜MCs （MMCs）扩张，MMCs衍生的胰蛋白酶血清水平升高。这导致肠道通透性增加，从而促进抗原吸收，从而导致口服过敏反应。从机制上讲，这些事件是由肠道级联反应驱动的，其中白细胞介素(IL)-17细胞因子减少导致生态失调，从而推动IL-25的产生。IL-25的增加增加了辅助性T (Th)2的产生，从而扩大了MMCs和加重了口服过敏反应。

此外，dock8缺陷T调节性（Treg）细胞抑制肠道IL-4产生和MC扩增的失败使夸张的过敏反应不受约束。这些结果表明微生物组、粘膜T细胞和MCs之间的多方面协调可以限制口服过敏反应。

据悉，免疫球蛋白E（IgE）介导的肥大细胞（MCs）释放介质驱动食物过敏，肠道MCs负荷是疾病严重程度的重要决定因素。DOCK8缺陷患者极易发生食物过敏。

附：英文原文

Title: DOCK8 in T cells promotes Th17 and Treg cell functionality to restrain mucosal mast cells and limit susceptibility to oral anaphylaxis

Author: 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, Waleed Al-Herz, Talal A. Chatila, Fred D. Finkelman, Seth Rakoff-Nahoum, Raif S. Geha

Issue&Volume: 2025-06-25

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. 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.

DOI: 10.1016/j.immuni.2025.06.004

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00273-0