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

Authors

• Emily R Siniscalco
• Courtney Fisher
• Meng-Ping Lu
• Jessica D S Grassmann, The Jackson LaboratoryFollow
• Corinne D Mack
• Roukaya Yaakoubi
• Danielle Jacobsen
• Qian Chen
• Donguk Lee
• Priya Rajamanimuthu
• Tregony Simoneau
• Kahn Preece
• Paul Gray
• Satoshi Okada
• Bertrand Boisson
• Basak Kayaoglu
• Jeffrey Danielson
• Alexandra F Freeman
• Jean-Laurent Casanova
• Talal A Chatila
• Helen C Su
• Cindy S Ma
• Adam Williams, The Jackson LaboratoryFollow
• Stephanie C Eisenbarth
• Uthaman Gowthaman

Document Type

Article

Publication Date

3-2-2026

Original Citation

Siniscalco E, Fisher C, Lu M, Grassmann J, Mack C, Yaakoubi R, Jacobsen D, Chen Q, Lee D, Rajamanimuthu P, Simoneau T, Preece K, Gray P, Okada S, Boisson B, Kayaoglu B, Danielson J, Freeman A, Casanova J, Chatila T, Su H, Ma C, Williams A, Eisenbarth S, Gowthaman U. DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells. J Exp Med. 2026;223(3):e20241707.

Keywords

JGM, Animals, STAT3 Transcription Factor, Guanine Nucleotide Exchange Factors, Immunoglobulin E, Mice, T Follicular Helper Cells, Mice, Knockout, Humans, Cell Differentiation, Mice, Inbred C57BL, Job Syndrome, T-Lymphocytes, Regulatory, GATA3 Transcription Factor, Peanut Hypersensitivity

JAX Source

J Exp Med. 2026;223(3):e20241707.

ISSN

1540-9538

PMID

41604592

DOI

https://doi.org/10.1084/jem.20241707

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.