title: Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis.
abstract: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis.
  
  
  
  To identify T-cell-dependent mechanisms that are protective in tuberculosis.
  
  
  
  Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood.
  
  
  
  At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-γ-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%).
  
  
  
  Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Busch
authors.affiliation: 2 Division of Clinical Infectious Diseases, German Center for Infection Research, Borstel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herzmann
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kallert
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Höfer
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mayer
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Zenk
authors.affiliation: 3 Institute for Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Muche
authors.affiliation: 2 Division of Clinical Infectious Diseases, German Center for Infection Research, Borstel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: 4 Harvard School of Public Health, Boston, Massachusetts; and.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Bloom
authors.affiliation: 5 Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: 1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Stenger
mesh_terms: D005434:Flow Cytometry; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control
chemical_list: D008070:Lipopolysaccharides; C050016:lipoarabinomannan
keywords: cytotoxicity; glycolipid antigens; infectious immunology; unconventional T cells