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Only a Subset of Phosphoantigen-Responsive ₉₂ T Cells Mediate Protective Tuberculosis Immunity¹

Charles T. Spencer^*,, Getahun Abate^*, Azra Blazevic^* and Daniel F. Hoft^2,*,

^* Department of Internal Medicine and Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO 63104

Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin (BCG) induce potent expansions of human memory V₉⁺V₂⁺ T cells capable of IFN- production, cytolytic activity, and mycobacterial growth inhibition. Certain phosphoantigens expressed by mycobacteria can stimulate ₉₂ 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 ₉₂ T cells potently inhibit intracellular mycobacterial growth, phosphoantigen-activated ₉₂ T cells fail to inhibit mycobacteria, although both develop similar effector cytokine and cytolytic functional capacities. ₉₂ 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 ₉₂ T cells. Testing this hypothesis, we compared the TCR sequence diversity of ₉₂ T cells expanded with BCG-infected vs phosphoantigen-treated dendritic cells. BCG-stimulated ₉₂ T cells displayed a more restricted TCR diversity than phosphoantigen-activated ₉₂ T cells. In addition, only a subset of phosphoantigen-activated ₉₂ T cells functionally responded to mycobacteria-infected dendritic cells. Furthermore, differential inhibitory functions of BCG- and phosphoantigen-activated ₉₂ 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 ₉₂ T cells, and provide the first indication that ₉₂ T cells can develop pathogen specificity similar to β T cells. Specific targeting of protective ₉₂ T cell subsets will be important for future tuberculosis vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This investigation was supported by National Institutes of Health Vaccine Treatment and Evaluation Unit Contract NO1-AI-25464 (to D.F.H., Co-investigator) and National Institutes of Health R01-AI-48391 (to D.F.H., Principal Investigator).

² Address correspondence and reprint requests to Dr. Daniel F. Hoft, Division of Immunobiology, Departments of Internal Medicine and Molecular Microbiology, Saint Louis University Health Sciences Center, 1100 South Grand Boulevard. DRC-807, St. Louis, MO 63104. E-mail address: hoftdf{at}slu.edu

³ Abbreviations used in this paper: BCG, M. bovis bacillus Calmette Guérin; AN, absolute number; BrHPP, bromohydrin pyrophosphate; DC, dendritic cell; DOXP, 1-deoxy-D-xylulose 5-phosphate, HMB-PP, (E)-4-hydroxy-3-methyl-but-enyl-pyrophosphate; IPP, isopentenyl pyrophosphate; MEP, 2-C-methyl-D-erythritol 4-phosphate; MtbWL, M. tuberculosis whole lysate; MOI, multiplicity of infection; Pam₃Cys, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys₄-OH, 3HCl; polyI:C, polyinosinic:polycytidylic acid; PPD, purified protein derivative; rhIL-2, recombinant human IL-2; TB, tuberculosis.

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