γδ T cells: bridging innate and adaptive immunity in development, tissue residency, and disease

Abstract

γδ T cells are a unique lymphocyte lineage that bridges innate and adaptive immunity through MHC-unrestricted recognition of phosphoantigens, lipids, and stress-induced proteins. Their tissue-resident subsets, shaped by Vγ/Vδ chain usage, play essential roles in barrier surveillance, tissue homeostasis, and host defense.This review synthesizes recent advances that fundamentally reshape our understanding of γδ T cell biology. We highlight two conceptual frameworks: (1) dual recognition modalities of γδ TCRs, distinguishing structurally resolved ligand interactions from functionally supported recognition; and (2) a developmental wave model in which TCR signal strength and transcriptional networks program effector fates. Mouse and human studies are presented in dedicated species-specific sections and tables, with explicit attention to species-specific nomenclature and evidence levels.We cover γδ T cell development, tissue-resident programs, antigen recognition mechanisms (including butyrophilin-mediated phosphoantigen sensing, antibody-like foreign antigen recognition, and intracellular self-protein recognition), and the dual roles of γδ T cells in infection, cancer, and chronic inflammation. Therapeutic applications—adoptive transfer, CAR-engineered cells, and extracellular-vesicle vaccines—are critically appraised against current clinical evidence.Finally, we identify major unanswered questions: the complete γδ TCR ligand repertoire, the mechanisms maintaining tissue residency, and the translational gaps between mouse models and human disease. This review provides a structured framework for understanding γδ T cells as pivotal connectors of innate and adaptive immunity.