Front Immunol. 2026 Jun 16;17:1854442. doi: 10.3389/fimmu.2026.1854442. eCollection 2026.
ABSTRACT
DOCK8 (dedicator of cytokinesis 8) is a prominent member of the DOCK-C subfamily and functions as an atypical guanine nucleotide exchange factor (GEF). It primarily activates Rho family small GTPases-most notably Cdc42-to orchestrate cytoskeletal remodeling, and it integrates multiple key signaling pathways to preserve the functional integrity of immune cells. Recent work has established DOCK8 as a central player in both innate and adaptive immunity. In T cells, DOCK8 contributes to migration, immunological synapse assembly, lineage specification, and long-term survival, thereby supporting antiviral defense and immune homeostasis. In B cells, it fine-tunes BCR signaling, amplifies CD19-driven signals, coordinates metabolic reprogramming, and facilitates germinal center reactions, all of which underpin humoral immunity and immunological memory. In NK cells, DOCK8 influences cytotoxic activity and tissue localization by modulating immunological synapse architecture and proximal receptor signaling. In dendritic cells and macrophages, it helps regulate chemotactic migration and immune activation by precisely controlling Cdc42 activity and cytoskeletal dynamics. Mechanistically, DOCK8 serves as a signaling hub that integrates inputs from the TCR, BCR, and Toll-like receptors, coordinating the establishment of cell polarity, directed migration, immunological synapse stability, and effector function. Deficiency of DOCK8 leads to a complex immunodeficiency syndrome characterized by impaired immune surveillance, heightened susceptibility to viral, bacterial, and fungal infections, as well as allergic manifestations and disrupted immune tolerance. Although considerable progress has been made in understanding DOCK8, the integrated mechanisms operating across different immune cell types and signaling networks still await systematic elucidation. Future investigations should focus on dissecting multi-tiered signaling networks and exploring targeted interventional strategies.
PMID:42382764 | PMC:PMC13314484 | DOI:10.3389/fimmu.2026.1854442