T cell repertoire in tuberculosis: selective anergy to an immunodominant epitope of the 38-kDa antigen in patients with active disease

Authors

  • Hans-M. Vordermeier,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • David P. Harris,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Giuseppe Friscia,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Eulogia Román,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Heljä-Marja Surcel,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Carlos Moreno,

    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Geoffrey Pasvol,

    1. Royal Postgraduate Medical School, Hammersmith Hospital and Unit of Infectious Diseases and Tropical Medicine, St. Mary's Hospital Medical School, Northwick Park Hospital, London
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  • Juraj Ivanyi

    Corresponding author
    1. MRC Tuberculosis and Related Infections Unit, St. Mary's Hospital Medical School, Northwick Park Hospital, London
    • MRC Tuberculosis and Related Infections Unit, Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Road, London W12 OHS, GB
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Abstract

It is generally accepted that both host protection and pathogenic reactions in tuberculosis are mediated by T lymphocytes. However, little is known about the structures and discreet functions of epitopes stimulating the immune response. In this study, proliferative responses of blood T lymphocytes to synthetic peptides derived from the sequence of the 38-kDa antigen from Mycobacterium tuberculosis have been investigated in 41 healthy individuals and in 36 patients with active tuberculosis. Of the healthy purified protein derivative (PPD)-positive donors, 90% responded to a permissively recognized peptide, 38.G (residues 350–359), located at the carboxy terminus of the molecule. Four other permissively recognized epitopes of this molecule (38.A, 38.I, 38.E, 38.K) were stimulatory for more then 50% of healthy PPD-positive individuals. Patients with lymphatic tuberculosis responded to these peptides in a similar manner. In contrast, we observed a selective anergy to stimulation with peptide 38.G in the majority of patients with pulmonary (11% responders) and nonlymphatic extrapulmonary tuberculosis (25% responders). The lack of responsiveness to 38.G was epitope specific since the degree of responsiveness to the other four permissively recognized peptide epitopes was similar for patients and PPD-positive controls. Using the PEPSCAN technology and truncated peptides, the core epitope of 38.G was localized to a peptide 10 amino acids long (HFQPLPPAVV). This minimal structure was capable of inducing a proliferative response in all healthy 38.G responders tested. The mechanisms influencing this epitope-specific anergy in patients could give new insights into the immunopathogenesis of tuberculosis.

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