Abstract
Vgamma9Vdelta2+ T cells (gammadelta T cells) are activated by Mycobacterium tuberculosis and recognize mycobacterial nonpeptide phosphoantigens. The role of antigen-presenting cells in the processing and presentation of phosphoantigens to Vgamma9Vdelta2+ T cells is not understood. We analyzed the role of macrophages for activation of gammadelta T cells by a new synthetic phosphoantigen bromohydrin pyrophosphate (BrHPP) and M. tuberculosis. Macrophages greatly increased gammadelta T-cell activation by both BrHPP and M. tuberculosis. Fixation of macrophages before infection demonstrated that uptake of M. tuberculosis was required for presentation to gammadelta T cells. Antigens of M. tuberculosis remained stably associated with macrophage surface and were not removed by paraformaldehyde fixation or washing. Macrophages processed M. tuberculosis for gammadelta T cells through a brefeldin A-insensitive pathway, suggesting that transport through the endoplasmic reticulum and Golgi complex of a putative presenting molecule is not important in the early processing of M. tuberculosis antigens for gammadelta T cells. Processing of M. tuberculosis was not eliminated by chloroquine, indicating that processing of gammadelta antigens is not dependent on acidic pH in the lysosomes. Chloroquine treatment of BrHPP-pulsed macrophages increased activation of gammadelta T cells. Ammonium chloride treatment of macrophages did not increase reactivity of gammadelta T cells to BrHPP, indicating that the effect of chloroquine was independent of pH changes in endosomes. Chloroquine, by inhibiting membrane traffic, may increase association and retention of phosphoantigens with cell surface membrane molecules on macrophages.
Highlights
Mycobacterium tuberculosis is an intracellular pathogen that infects and resides within mononuclear phagocytes
We analyzed the role of macrophages for activation of ␥␦ T cells by a new synthetic phosphoantigen bromohydrin pyrophosphate (BrHPP) and M. tuberculosis
Phosphoantigens can be recognized without requiring uptake or presentation by professional antigen-presenting cells (APC); ␥␦ T-cell responses to intact M. tuberculosis bacilli depend on accessory cells [11, 19, 47, 51]
Summary
Mycobacterium tuberculosis is an intracellular pathogen that infects and resides within mononuclear phagocytes. The recently identified 3-formyl-1-butyl pyrophosphate is likely a biosynthetic precursor of mycobacterial IPP, eliciting ␥␦ T-cell activation and targeting responses to infected cells [8]. This compound is produced in very small amounts in slow-growing mycobacteria such as M. tuberculosis and accumulates to submicromolar concentrations in culture media from fast-growing mycobacterial species. Phosphoantigens did not require intracellular processing but remained stably associated on the surface of macrophages in the presence of chloroquine, suggesting an interaction between BrHPP and cell membrane molecules. Our results support a model in which phosphoantigens associate with host molecules on the surface of macrophages and membrane traffic regulates the availability of these phosphoantigens for ␥␦ T-cell recognition
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