title: Massive monoclonal expansion of CD4 T-cells specific for a Mycobacterium tuberculosis ESAT-6 peptide.
abstract: T-cell responses towards tuberculin (purified protein derivative; PPD) or the Mycobacterium tuberculosis-specific antigens early secretory antigenic target (ESAT)-6 and culture filtrate protein-10 are indicative of prior contact with mycobacterial antigens. In this study, we investigated the exceptional case of a 75-yr-old patient who devoted more than one-third of his CD4 T-cells against PPD and ESAT-6. Antigen-specific T-cells were characterised using flow cytometric intracellular cytokine staining, ELISPOT assay, proliferation assays, and T-cell receptor spectratyping. T-cell frequencies were far above those found in age-matched controls (median 0.33%, range 0.05-6.32%) and remained at high levels for >2 yrs. The patient initially presented with haemoptysis, but active tuberculosis was ruled out by repeated analysis of sputum and bronchoalveolar lavage fluid. Skin testing was negative and haemoptyses did not have a M. tuberculosis-related aetiology. Phenotypical and functional properties of specific T-cells were consistent with a terminally differentiated effector-memory phenotype with capacity to produce interferon-γ, interleukin-2 and tumour necrosis factor-α. Epitope mapping showed that the CD4 T-cells were directed against a single peptide from ESAT-6 (amino acid 5-20) that was presented in context of HLA-DR. T-cell receptor Vβ-spectratyping and sequencing of specific CD4 T-cells revealed a prominent peak fraction of monoclonal origin. In conclusion, similar to monoclonal gammopathies of undetermined significance, this may represent the first T-cell counterpart with known specificity against M. tuberculosis.
authors.affiliation: Dept of Transplant and Infection Immunology, Saarland University, Homburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hodapp
authors.forename: Urban
authors.initials: U
authors.lastname: Sester
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mack
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wiech
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Martina
authors.initials: M
authors.lastname: Sester
mesh_terms: D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018604:Epitope Mapping; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010265:Paraproteinemias / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D014373:Tuberculin; C072681:Mycobacterium tuberculosis antigens