Only a Subset of Phosphoantigen-Responsive γ9δ2 T Cells Mediate Protective Tuberculosis Immunity

Abstract

Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin (BCG) induce potent expansions of human memory Vγ9+Vδ2+ T cells capable of IFN-γ production, cytolytic activity, and mycobacterial growth inhibition. Certain phosphoantigens expressed by mycobacteria can stimulate γ9δ2 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 γ9δ2 T cells potently inhibit intracellular mycobacterial growth, phosphoantigen-activated γ9δ2 T cells fail to inhibit mycobacteria, although both develop similar effector cytokine and cytolytic functional capacities. γ9δ2 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 γ9δ2 T cells. Testing this hypothesis, we compared the TCR sequence diversity of γ9δ2 T cells expanded with BCG-infected vs phosphoantigen-treated dendritic cells. BCG-stimulated γ9δ2 T cells displayed a more restricted TCR diversity than phosphoantigen-activated γ9δ2 T cells. In addition, only a subset of phosphoantigen-activated γ9δ2 T cells functionally responded to mycobacteria-infected dendritic cells. Furthermore, differential inhibitory functions of BCG- and phosphoantigen-activated γ9δ2 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 γ9δ2 T cells, and provide the first indication that γ9δ2 T cells can develop pathogen specificity similar to αβ T cells. Specific targeting of protective γ9δ2 T cell subsets will be important for future tuberculosis vaccines.