DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-12-12
DOI
https://doi.org/10.1084/jem.20241707
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
0.00
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article

DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells

Paul Gray, Jeffrey J. Danielson, Uthaman Gowthaman, Tregony Simoneau et al.
The Journal of Experimental Medicine
Immunodeficiency and Autoimmune Disorders
article

DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells

Paul Gray, Jeffrey J. Danielson, Uthaman Gowthaman, Tregony Simoneau, Adam Williams, Başak Kayaoğlu, Meng-Ping Lu, Roukaya Yaakoubi, Corinne D. Mack, Satoshi Okada, Kahn Preece, Stephanie C. Eisenbarth, Courtney Fisher, Emily R. Siniscalco, Jessica Grassmann, Cindy S. Ma, Bertrand Boisson, Alexandra F. Freeman, Donguk Lee, Talal A. Chatila, Qian Chen, Jean-Laurent Casanova, Priya Rajamanimuthu
article en

Abstract

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

The Journal of Experimental MedicineVol. 223(3)
Northwestern University (US), Hiroshima University (JP), Boston Children's Hospital (US), The University of Sydney (AU), Howard Hughes Medical Institute (US), Harvard University (US), Garvan Institute of Medical Research (AU), Inserm (FR), University of Massachusetts Chan Medical School (US), Université Paris Cité (FR), Hospital for Sick Children (CA), UNSW Sydney (AU), Yale University (US), Hospital for Sick Children Pediatric Center (US), Jackson Laboratory (US), Sydney Children's Hospital (AU), National Institute of Allergy and Infectious Diseases (US), John Hunter Children's Hospital (AU), Sydney Local Health District (AU), Boston Children's Museum (US), Human Genetic of Infectious Diseases (FR), Institut des Maladies Génétiques Imagine (FR), Rockefeller University (US)
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