In vivo gammadelta T cell priming to mycobacterial antigens by primary Mycobacterium tuberculosis infection and exposure to nonpeptidic ligands.
BACKGROUND
The recognition of phosphorylated nonpeptidic microbial metabolites by Vgamma9Vdelta2 T cells does not appear to require the presence of MHC molecules or antigen processing, permitting rapid responses against microbial pathogens. These may constitute an important area of natural anti-infectious immunity. To provide evidence of their involvement in immune reactivities against mycobacteria, we measured the responsiveness of peripheral blood Vgamma9Vdelta2 T cells in children with primary Mycobacterium tuberculosis (MTB) infections.


METHODS
Peripheral blood mononuclear cells from 22 children with MTB infections and 16 positivity of tuberculin (PPD)-negative healthy children were exposed to nonpeptidic antigens in vitro and the reactivity of the Vgamma9Vdelta2 T cell subset with these antigens was determined using proliferation and cytokine assays. Also, responses of gammadelta T cells from rhesus monkeys stimulated with phosphoantigens in vivo were measured.


RESULTS
The Vgamma9Vdelta2 T cell responses were highly increased in infected children in comparison with age-matched controls. This augmented Vgamma9Vdelta2 T cell reactivity subsided after successful antibiotic chemotherapy, suggesting that persistent exposure to mycobacterial antigens is required for the maintenance of gammadelta T cell activation in vivo. The in vivo reactivity of Vgamma9Vdelta2 T cells to phosphoantigens was also analyzed in a rhesus monkey model system. Intravenous injections of phosphoantigens induced an activated state of simian Vgamma9Vdelta2 T cells which decreased after 2 months, i.e., with a time course similar to that seen in MTB-infected children.


CONCLUSIONS
The increased reactivity of Vgamma9Vdelta2 T cells to phosphoantigens appears to be dependent on constant antigenic exposure. Consequently, the assessment of Vgamma9Vdelta2 responses may be useful for monitoring the efficacy of antimycobacterial therapies.
Poccia
F
F
Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, University of Wisconsin Comprehensive Cancer Center, and Wisconsin Regional Primate Research Center, Madison, Wisconsin 53706, USA.
Malkovsky
M
M
Pollak
A
A
Colizzi
V
V
Sireci
G
G
Salerno
A
A
Dieli
F
F
D000818:Animals; D000941:Antigens / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D011756:Diphosphates / Q000494:pharmacology; D005260:Female; D045782:Hemiterpenes; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013403:Sugar Phosphates / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000941:Antigens; D000942:Antigens, Bacterial; D011756:Diphosphates; D045782:Hemiterpenes; D008024:Ligands; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013403:Sugar Phosphates; D014409:Tumor Necrosis Factor-alpha; C004809:isopentenyl pyrophosphate; D007371:Interferon-gamma