title: Highly focused T cell responses in latent human pulmonary Mycobacterium tuberculosis infection.
abstract: The elucidation of the molecular and immunological mechanisms mediating maintenance of latency in human tuberculosis aids to develop more effective vaccines and to define biologically meaningful markers for immune protection. We analyzed granuloma-associated lymphocytes (GALs) from human lung biopsies of five patients with latent Mycobacterium tuberculosis (MTB) infection. MTB CD4+ and CD8+ T cell response was highly focused in the lung, distinct from PBL, as assessed by TCR-CDR3 spectratyping coupled with a quantitative analysis of TCR VB frequencies. GALs produced IFN-gamma in response to autologous macrophages infected with MTB and to defined MTB-derived HLA-A2-presented peptides Ag85a242-250, Ag85b199-207, early secreted antigenic target 6 (ESAT-6)28-36, 19-kDa Ag88-97, or the HLA-DR-presented ESAT-6(1-20) epitope. Immune recognition of naturally processed and presented MTB epitopes or the peptide ESAT-6(1-20) could be linked to specific TCR VB families, and in two patients to unique T cell clones that constituted 19 and 27%, respectively, of the CD4+ and 17% of the CD8+ GAL population. In situ examination of MTB-reactive GALs by tetramer in situ staining and confocal laser-scanning microscopy consolidates the presence of MHC class I-restricted CD8+ T cells in MTB granuloma lesions and supports the notion that clonally expanded T cells are crucial in immune surveillance against MTB.
authors.affiliation: Department of Medical Microbiology, University of Mainz, Mainz, Germany.
authors.forename: Glenn
authors.initials: G
authors.lastname: Tully
authors.forename: Cornelius
authors.initials: C
authors.lastname: Kortsik
authors.forename: Hanni
authors.initials: H
authors.lastname: Höhn
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Zehbe
authors.forename: W E
authors.initials: WE
authors.lastname: Hitzler
authors.forename: Claudia
authors.initials: C
authors.lastname: Neukirch
authors.forename: Kirsten
authors.initials: K
authors.lastname: Freitag
authors.forename: Klaus
authors.initials: K
authors.lastname: Kayser
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Maeurer
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006099:Granuloma / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma