title: Only a subset of phosphoantigen-responsive gamma9delta2 T cells mediate protective tuberculosis immunity.
abstract: Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin (BCG) induce potent expansions of human memory Vgamma(9)(+)Vdelta(2)(+) T cells capable of IFN-gamma production, cytolytic activity, and mycobacterial growth inhibition. Certain phosphoantigens expressed by mycobacteria can stimulate gamma(9)delta(2) T cell expansions, suggesting that purified or synthetic forms of these phosphoantigens may be useful alone or as components of new vaccines or immunotherapeutics. However, we show that while mycobacteria-activated gamma(9)delta(2) T cells potently inhibit intracellular mycobacterial growth, phosphoantigen-activated gamma(9)delta(2) T cells fail to inhibit mycobacteria, although both develop similar effector cytokine and cytolytic functional capacities. gamma(9)delta(2) T cells receiving TLR-mediated costimulation during phosphoantigen activation also failed to inhibit mycobacterial growth. We hypothesized that mycobacteria express Ags, other than the previously identified phosphoantigens, that induce protective subsets of gamma(9)delta(2) T cells. Testing this hypothesis, we compared the TCR sequence diversity of gamma(9)delta(2) T cells expanded with BCG-infected vs phosphoantigen-treated dendritic cells. BCG-stimulated gamma(9)delta(2) T cells displayed a more restricted TCR diversity than phosphoantigen-activated gamma(9)delta(2) T cells. In addition, only a subset of phosphoantigen-activated gamma(9)delta(2) T cells functionally responded to mycobacteria-infected dendritic cells. Furthermore, differential inhibitory functions of BCG- and phosphoantigen-activated gamma(9)delta(2) T cells were confirmed at the clonal level and were not due to differences in TCR avidity. Our results demonstrate that BCG infection can activate and expand protective subsets of phosphoantigen-responsive gamma(9)delta(2) T cells, and provide the first indication that gamma(9)delta(2) T cells can develop pathogen specificity similar to alphabeta T cells. Specific targeting of protective gamma(9)delta(2) T cell subsets will be important for future tuberculosis vaccines.
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Spencer
authors.forename: Getahun
authors.initials: G
authors.lastname: Abate
authors.forename: Azra
authors.initials: A
authors.lastname: Blazevic
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000276:immunology*; D002460:Cell Line; D002999:Clone Cells; D045782:Hemiterpenes / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology*; D009943:Organophosphorus Compounds / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology
chemical_list: D000942:Antigens, Bacterial; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate
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