In vivo gamma delta T cell priming to mycobacterial antigens by primary Mycobacterium tuberculosis infection and exposure to nonpeptidic ligands

Background: The recognition of phosphorylated nonpeptidic microbial metabol ites by V gamma 9V delta 2 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 re activities against mycobacteria, we measured the responsiveness of peripher al blood V gamma 9V delta 2 T cells in children with primary Mycobacterium tuberculosis (MTB) infections. Materials and 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 o f the V gamma 9V delta 2 T cell subset with these antigens was determined u sing proliferation and cytokine assays. Also, responses of gamma delta T ce lls from rhesus monkeys stimulated with phosphoantigens in vivo were measur ed. Results: The V gamma 9V delta 2 T cell responses were highly increased in i nfected children in comparison with age-matched controls. This augmented V gamma 9V delta 2 T cell reactivity subsided after successful antibiotic che motherapy, suggesting that persistent exposure to mycobacterial antigens is required for the maintenance of ya T cell activation in vivo. The in vivo reactivity of V gamma 9V delta 2 T cells to phosphoantigens was also analyz ed in a rhesus monkey model system. Intravenous injections of phosphoantige ns induced an activated state of simian V gamma 9V delta 2 T cells which de creased after 2 months, i.e., with a time course similar to that seen in MT B-infected children. Conclusions: The increased reactivity of V gamma 9V delta 2 T cells to phos phoantigens appears to be dependent on constant antigenic exposure. Consequ ently, the assessment of V gamma 9V delta 2 responses may be useful for mon itoring the efficacy of antimycobacterial therapies.