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

Erin Janssen¹, Mrinmoy Das², Jordan Butts³, Mohammed Alasharee³, Saikat Mukherjee³, Gabriel L Lozano⁴, Chitong Rao⁴, Andrew F Livingston⁵, Brian Woods³, Emma Smith³, Zachary Peters³, Elena Milin³, Maria A Beamer⁵, Hazel Wilkie⁶, Juan-Manuel Leyva-Castillo³, Christy Kam³, Ali Sobh⁷, Majed Dasouki⁸, Rima Hanna Wakim⁹, Ghassan Dbaibo⁹, Waleed Al-Herz¹⁰, Talal A Chatila³, Fred D Finkelman¹¹, Seth Rakoff-Nahoum⁴, Raif S Geha¹²

Affiliations

¹ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Department of Pediatrics, Michigan Medicine, Ann Arbor, MI 48109, USA. Electronic address: ejanssen@med.umich.edu.
² Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
³ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁵ Division of Rheumatology, Department of Pediatrics, Michigan Medicine, Ann Arbor, MI 48109, USA.
⁶ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 OAW, UK.
⁷ Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
⁸ Department of Genetics & Genomics, AdventHealth Medical Group Genomics and Personalized Health at Orlando, Orlando, FL 32803, USA.
⁹ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut 1107 2020, Lebanon.
¹⁰ Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City 13009, Kuwait.
¹¹ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹² Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: raif.geha@childrens.harvard.edu.

PMID: 40570852
PMCID: PMC12443339 (available on 2026-07-08)
DOI: 10.1016/j.immuni.2025.06.004

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

Erin Janssen et al. Immunity. 2025.

. 2025 Jul 8;58(7):1794-1810.e5.

doi: 10.1016/j.immuni.2025.06.004. Epub 2025 Jun 25.

Authors

Affiliations

¹ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Department of Pediatrics, Michigan Medicine, Ann Arbor, MI 48109, USA. Electronic address: ejanssen@med.umich.edu.
² Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
³ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁵ Division of Rheumatology, Department of Pediatrics, Michigan Medicine, Ann Arbor, MI 48109, USA.
⁶ Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 OAW, UK.
⁷ Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
⁸ Department of Genetics & Genomics, AdventHealth Medical Group Genomics and Personalized Health at Orlando, Orlando, FL 32803, USA.
⁹ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut 1107 2020, Lebanon.
¹⁰ Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City 13009, Kuwait.
¹¹ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
¹² Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: raif.geha@childrens.harvard.edu.

PMID: 40570852
PMCID: PMC12443339 (available on 2026-07-08)
DOI: 10.1016/j.immuni.2025.06.004

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.

Keywords: DOCK8; IL-4; anaphylaxis; dysbiosis; food allergy; intestinal microbiome; mast cells; passive anaphylaxis; regulatory T cells; tryptase.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Gupta RS, Warren CM, Smith BM, Blumenstock JA, Jiang J, Davis MM, and Nadeau KC (2019). The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States. Pediatrics 142, e20181235. 10.1542/peds.2018-1235. - DOI - PMC - PubMed
1. Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, and Holl JL (2011). The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 128, e9–e17. 10.1542/peds.2011-0204. - DOI - PubMed
1. Liu AH, Jaramillo R, Sicherer SH, Wood RA, Bock SA, Burks AW, Massing M, Cohn RD, and Zeldin DC (2010). National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005–2006. J. Allergy Clin. Immunol. 126, 798–806.e14. 10.1016/j.jaci.2010.07.026. - DOI - PMC - PubMed
1. Lack G, Fox D, Northstone K, and Golding J; Avon Longitudinal Study of Parents and Children Study Team. (2003). Factors Associated with the Development of Peanut Allergy in Childhood. N. Engl. J. Med. 348, 977–985. 10.1056/NEJMoa013536. - DOI - PubMed
1. Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, Sattentau QA, Comeau MR, Spergel JM, and Artis D (2014). Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. e1391–1396. J. Allergy Clin. Immunol. 133, 1390–1399.e6. 10.1016/j.jaci.2014.01.021. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical