Gut microbiota - γδT cells axis: mechanisms of immunoregulation and therapeutic opportunities.

Abstract

γδT cell subsets serve key roles within mucosal immunity. In the intestine, γδT cells account for approximately 10-18% of intraepithelial lymphocytes (IELs), highlighting their substantial representation in the mucosal immune compartment. This review covers the gut microbiota-intestinal γδT cell axis as a bidirectional communication network between tissue resident γδT cells in the intestinal epithelium and lamina propria and the local microbial community. Microbially derived cues and metabolites, including short-chain fatty acids (SCFAs), secondary bile acid, and tryptophan-derived indole compounds, can influence γδT cell maturation, differentiation and effector functions. Propionate has been reported to suppress IL-17 and IL-22 secretion by intestinal γδT cells through a histone deacetylase (HDAC)-dependent mechanism. In germ-free (GF) models, intestinal γδT cell populations are reduced by approximately 90% relative to conventionally colonized controls, indicating a marked influence of microbial exposure in this experimental setting while highlighting the need to avoid direct extrapolation to human intestinal γδT cell biology. Conversely, γδT cell-derived cytokines can influence epithelial integrity and the local microbial environment, although causal evidence for quantitative reshaping of the human intestinal microbiota remains limited. The novelty of this narrative Review lies not in proposing the gut microbiota-γδT cell axis as a new biological concept, but in providing an evidence-graded synthesis that integrates bidirectional regulation across experimental species, tissue compartments, γδT cell subsets, study designs, and levels of mechanistic support. This framework highlights where causal evidence is strongest, where human evidence remains associative, and where defined microbial metabolites, intestinal γδT cell subsets, and clinical outcomes have not yet been mechanistically connected.