title: Suboptimal Antigen Presentation Contributes to Virulence of Mycobacterium tuberculosis In Vivo.
abstract: Mycobacterium tuberculosis commonly causes persistent or chronic infection, despite the development of Ag-specific CD4 T cell responses. We hypothesized that M. tuberculosis evades elimination by CD4 T cell responses by manipulating MHC class II Ag presentation and CD4 T cell activation and tested this hypothesis by comparing activation of Ag85B-specific CD4 T cell responses to M. tuberculosis and M. bovis bacillus Calmette-Guérin (BCG) Pasteur in vivo and in vitro. We found that, although M. tuberculosis persists in lungs of immunocompetent mice, M. bovis BCG is cleared, and clearance is T cell dependent. We further discovered that M. tuberculosis-infected macrophages and dendritic cells activate Ag85B-specific CD4 T cells less efficiently and less effectively than do BCG-infected cells, in vivo and in vitro, despite higher production and secretion of Ag85B by M. tuberculosis. During BCG infection, activation of Ag85B-specific CD4 T cells requires fewer infected dendritic cells and fewer Ag-producing bacteria than during M. tuberculosis infection. When dendritic cells containing equivalent numbers of M. tuberculosis or BCG were transferred to mice, BCG-infected cells activated proliferation of more Ag85B-specific CD4 T cells than did M. tuberculosis-infected cells. Differences in Ag85B-specific CD4 T cell activation were attributable to differential Ag presentation rather than differential expression of costimulatory or inhibitory molecules. These data indicate that suboptimal Ag presentation contributes to persistent infection and that limiting Ag presentation is a virulence property of M. tuberculosis.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016;
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Grace
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016; and Department of Microbiology, New York University School of Medicine, New York, NY 10016 joel.ernst@med.nyu.edu.
authors.forename: Joel D
authors.identifier: http://orcid.org/0000-0001-9951-6207
authors.initials: JD
authors.lastname: Ernst
mesh_terms: D000217:Acyltransferases / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000637:transplantation; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D018417:Th1 Cells / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology; D037521:Virulence Factors / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D037521:Virulence Factors; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis