{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:47:58Z","timestamp":1785757678755,"version":"3.56.0"},"reference-count":158,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>V\u03b39V\u03b42 T cells constitute the predominant human circulating \u03b3\u03b4 T cell subset and serve as key mediators of anti-mycobacterial immunity through major histocompatibility complex (MHC)-unrestricted phosphoantigen recognition and rapid effector activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>\n                      This review evaluates V\u03b39V\u03b42 T cell biology in the context of tuberculosis (TB). We delineate the three-stage developmental pathway of V\u03b39V\u03b42 T cells in the postnatal thymus and the butyrophilin 3A1\/2A1 (BTN3A1\/BTN2A1)-mediated \u201cinside-out\u201d antigen sensing mechanism, noting the limitations of extrapolating\n                      <jats:italic>in vitro<\/jats:italic>\n                      findings to\n                      <jats:italic>in vivo<\/jats:italic>\n                      TB infection. The multifaceted activation networks\u2014involving TCR-dependent signaling, cytokine amplification, and accessory co-receptor pathways\u2014are examined in relation to distinct phases of\n                      <jats:italic>Mtb<\/jats:italic>\n                      infection. V\u03b39V\u03b42 T cells exert anti-TB protection through direct cytotoxicity (perforin\/granzyme B, granulysin, FasL\/TRAIL), cytokine-mediated immunoregulation, and orchestration of \u03b1\u03b2 T cell and dendritic cell responses; however, the functional significance of granulysin-dependent killing and the paradoxical V\u03b42\u2192V\u03b41 subset shift during chronic infection warrant further investigation.\n                      <jats:italic>Mtb<\/jats:italic>\n                      immune evasion through metabolic antigen camouflage and chronic infection-induced exhaustion is also analyzed. Emerging evidence for V\u03b39V\u03b42 T cell immunological memory\u2014including BCG-induced trained immunity and phosphoantigen-driven memory-like expansion in non-human primates \u2014provides 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>V\u03b39V\u03b42 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 \u03b3\u03b4 T cell biology offers a promising path toward clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1884056","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:19:25Z","timestamp":1785755965000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["V\u03b39V\u03b42 T cells in tuberculosis: protective immunity and translational perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhiyun","family":"Shi","sequence":"first","affiliation":[{"name":"Medical Experiment Center, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]},{"name":"Key Laboratory of Clinical Pathogenic Microorganisms, General Hospital of Ningxia Medical University","place":["Yinchuan, 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