In vivo γδ T Cell Priming to Mycobacterial Antigens by Primary Mycobacterium tuberculosis Infection and Exposure to Nonpeptidic Ligands

The recognition of phosphorylated nonpeptidic microbial metabolites by Vγ9Vδ2 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 Vγ9Vδ2 T cells in children with primary Mycobacterium tuberculosis (MTB) infections. 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 Vγ9Vδ2 T cell subset with these antigens was determined using proliferation and cytokine assays. Also, responses of γδ T cells from rhesus monkeys stimulated with phosphoantigens in vivo were measured. The Vγ9Vδ2 T cell responses were highly increased in infected children in comparison with age-matched controls. This augmented Vγ9Vδ2 T cell reactivity subsided after successful antibiotic chemotherapy, suggesting that persistent exposure to mycobacterial antigens is required for the maintenance of γδ T cell activation in vivo. The in vivo reactivity of Vγ9Vδ2 T cells to phosphoantigens was also analyzed in a rhesus monkey model system. Intravenous injections of phosphoantigens induced an activated state of simian Vγ9Vδ2 T cells which decreased after 2 months, i.e., with a time course similar to that seen in MTB-infected children. The increased reactivity of Vγ9Vδ2 T cells to phosphoantigens appears to be dependent on constant antigenic exposure. Consequently, the assessment of Vγ9Vδ2 responses may be useful for monitoring the efficacy of antimycobacterial therapies.