Vγ9Vδ2 T cells in tuberculosis: protective immunity and translational perspectives.

BACKGROUND: Vγ9Vδ2 T cells constitute the predominant human circulating γδ T cell subset and serve as key mediators of anti-mycobacterial immunity through major histocompatibility complex (MHC)-unrestricted phosphoantigen recognition and rapid effector activation. SUMMARY: This review evaluates Vγ9Vδ2 T cell biology in the context of tuberculosis (TB). We delineate the three-stage developmental pathway of Vγ9Vδ2 T cells in the postnatal thymus and the butyrophilin 3A1/2A1 (BTN3A1/BTN2A1)-mediated "inside-out" antigen sensing mechanism, noting the limitations of extrapolating in vitro findings to in vivo TB infection. The multifaceted activation networks-involving TCR-dependent signaling, cytokine amplification, and accessory co-receptor pathways-are examined in relation to distinct phases of Mtb infection. Vγ9Vδ2 T cells exert anti-TB protection through direct cytotoxicity (perforin/granzyme B, granulysin, FasL/TRAIL), cytokine-mediated immunoregulation, and orchestration of αβ T cell and dendritic cell responses; however, the functional significance of granulysin-dependent killing and the paradoxical Vδ2→Vδ1 subset shift during chronic infection warrant further investigation. Mtb immune evasion through metabolic antigen camouflage and chronic infection-induced exhaustion is also analyzed. Emerging evidence for Vγ9Vδ2 T cell immunological memory-including BCG-induced trained immunity and phosphoantigen-driven memory-like expansion in non-human primates -provides a rationale for novel vaccine strategies, although the translatability of these findings to human TB remains to be established. Translational approaches, including synthetic phosphoantigen prodrugs, BTN-targeted monoclonal antibodies, and adoptive cell therapy, are assessed for their clinical potential against drug-resistant TB, with discussion of current limitations. CONCLUSION: Vγ9Vδ2 T cells offer distinct advantages for TB immunotherapy and vaccine design, but significant translational barriers remain. Future studies must address subset heterogeneity across infection stages, the epigenetic and metabolic reprogramming governing functional fate decisions, standardized correlates of protection, and BTN-targeted strategies validated in TB-specific preclinical models. The integration of single-cell multi-omics and CRISPR-based functional screening with γδ T cell biology offers a promising path toward clinical translation.