The Moody laboratory conducts translational research into the mechanisms by which T cells and CD1 proteins influence human immune response. CD1 proteins have been conserved throughout mammalian evolution and resemble MHC class I proteins. However, CD1 proteins capture lipids, rather than peptides,…
more for presentation to T cells. Using liquid chromatography-mass spectrometry, we discovered foreign glycolipid antigens that bind to CD1 proteins, including glucose monomycolates, mannosyl phosphomycoketides and dideoxymycobactin lipopeptides. These studies were the first to identify foreign antigens presented by CD1a and CD1c proteins and provided evidence for lipid-specific T cell responses in vivo in humans. We have used structure-function studies to determine how individual chemical elements of these antigens contribute to binding to CD1 proteins and to T cell antigen receptors. Through genetic, biochemical and clinical studies, we identified mycobacterial enzymes that synthesize these antigens, including polyketide synthase 12 and mycobactin synthase B. Current studies seek to understand the duration and magnitude of lipid-specific T cell responses in human patients with tuberculosis, HIV, Graves’ disease and Hashimoto’s thyroiditis. Further, we have developed a mass spectrometric profiling system to identify small molecules in the mycobacterial cell wall that are altered during acquisition of multi-drug resistant or after deletion of resistance-conferring genes. The long term goal of this work is to develop lipids as the basis for immunodiagnostic tests and preventative vaccines and to understand how amphipathic drugs are transported across the mycobacterial cell wall.
less