Dock8 regulates Th2 cell differentiation through ANXA1.

Dedicator of Cytokinesis 8 (DOCK8), a member of the DOCK family of guanine nucleotide exchange factors, serves as a key factor in managing the Rho GTPases activity, notably Cdc42 and Rac1, which control key cellular processes, including migration, adhesion, and phagocytosis. Mutations in the DOCK8 gene cause autosomal recessive hyper-IgE syndrome (AR-HIES), a primary immunodeficiency disorder characterized by elevated serum IgE levels, eczema, recurrent infections, and defective immune responses. In this study, a CRISPR/Cas9-generated Dock81281&1282 TG deletion mutation mouse model was constructed to investigate the immunological consequences of Dock8 deficiency. Our results demonstrate that Dock8 is essential for the peripheral homeostasis of T cells, particularly T follicular helper (Tfh), Th2, and regulatory T cells (Treg). Notably, in Dock8 mutant mice, both Th2 and Tfh cells were elevated, and they collaboratively promote IgE production. Additionally, we identified that Annexin A1 (ANXA1) enhances Th2 cell differentiation in Dock8 mutants, suggesting its potential role in restoring immune balance. These findings provide a refined understanding of the molecular mechanisms associated with DOCK8-related immune deficiencies and highlight potential therapeutic strategies for managing AR-HIES.