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.