1330. Human T Cells Recognize CD1 and M. tuberculosis antigens in vivo
Session: Symposium: Immunity in Tuberculosis
Saturday, October 22, 2011: 2:45 PM
Room: 204AB
Anne G Kasmar1, Ildiko van Rhijn1,2, Tan-Yun Cheng1, Marie Turner3, Chetan Seshadri1, Andre Schiefner4, Ravi C Kalathur4, John W Annand1, Annemieke de Jong1, John Shires5, Luis Leon1, Michael Brenner1, Ian A Wilson4,John Altman5, and D Branch Moody1*+

1Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital

2Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Netherlands

3Tuberculosis Treatment Unit, Lemuel Shattuck Hospital

4Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute

5Emory Vaccine Center

CD1 proteins have been conserved throughout mammalian evolution and resemble MHC class I proteins in structure. However, CD1 proteins capture lipids, rather than peptides, for presentation to T cells. Using liquid chromatography-mass spectrometry methods, we discovered several foreign glycolipid antigens that bind to CD1 proteins, including glucose monomycolates, mannosyl phosphomycoketides, dideoxymycobactin lipopeptides and phenyl pentamethyldihydro-benzofuran sulfonates. After published studies indicated that lipid restricted T cells are activated in patients, we sought to develop tetramers to directly track CD1-restricted T cells ex vivo.  Using CD1 tetramers bound to glycolipid antigens, we are studying the co-receptors, NK markers and T cell receptor structure of responding T cells.  These studies investigate the general hypothesis that natural tuberculosis infection generates memory responses to lipid antigens in vivo and may provide new diagnositic tests for tuberculosis.



D. Branch Moody, MD, Brigham and Women's Hospital, Boston, MA

The Moody laboratory conducts basic research into the molecular mechanisms of T cell activation by CD1 proteins and lipid antigens. CD1 proteins have been conserved throughout mammalian evolution and resemble MHC class I proteins in structure. However, CD1 proteins capture lipids, rather than peptides, for presentation to T cells. Using liquid chromatography-mass spectrometry methods, we discovered several foreign glycolipid antigens that bind to CD1 proteins, including glucose monomycolates, mannosyl phosphomycoketides, dideoxymycobactin lipopeptides and phenyl pentamethyldihydro-benzofuran sulfonates. These studies were the first to identify foreign antigens presented by CD1a and CD1c proteins and provide 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. These studies support the general conclusion that the carbohydrate and peptide moieties of antigens lie on the outer surface of CD1, where they are presented to T cell antigen receptors. This basic information has contributed to the design and chemical synthesis of lipid stimulants for human T cells. Further, discovery of these molecules has supported our research into the cellular mechanisms that regulate T cell responses to self and foreign antigens. We have shown that antecedent activation of Toll-like receptor 2 on human dendritic cells increases CD1 protein synthesis and the overall efficiency of presentation of lipids to T cells. Also, we found that the length of aliphatic hydrocarbon chains of these antigens influence their insertion into the antigen binding grooves of CD1 proteins. Through genetic, biochemical and clinical studies, we identified mycobacterial enzymes that synthesize these antigens, including polyketide synthase 12 and mycobactin synthase G. We have measured the influence of these antigenic lipids on mycobacterial growth and pathogenicity in tissues, and we monitored lipid-specific T cell response during natural infections in humans. In addition, we have developed a mass spectrometry based system for nearly comprehensive profiling of mycobacterial cell walls in response to genetic and environmental variables. Current translational studies seek to understand the duration and magnitude of lipid-specific T cell responses in human patients with tuberculosis, HIV, Graves’ disease, Hashimoto’s thyroiditis, Lyme disease and drug hypersensitivity reactions. The long term goal of this work is to develop lipids as the basis for immunodiagnostic tests and preventative vaccines. This research is incorporated into patient care as an attending physician in the Division of Rheumatology, Immunology and Allergy in the Department of Internal Medicine at the Brigham and Women’s Hospital.



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