title: Patients with multidrug-resistant tuberculosis display impaired Th1 responses and enhanced regulatory T-cell levels in response to an outbreak of multidrug-resistant Mycobacterium tuberculosis M and Ra strains.
abstract: In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-gamma) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4+ and CD8+ T cells from MDR- and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN-gamma expression and CTL activity in TB patients, with M- and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles.
authors.affiliation: Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Geffner
authors.forename: Noemí
authors.initials: N
authors.lastname: Yokobori
authors.forename: Juan
authors.initials: J
authors.lastname: Basile
authors.forename: Pablo
authors.initials: P
authors.lastname: Schierloh
authors.forename: Luciana
authors.initials: L
authors.lastname: Balboa
authors.forename: María Mercedes
authors.initials: MM
authors.lastname: Romero
authors.forename: Viviana
authors.initials: V
authors.lastname: Ritacco
authors.forename: Marisa
authors.initials: M
authors.lastname: Vescovo
authors.forename: Pablo
authors.initials: P
authors.lastname: González Montaner
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lopez
authors.forename: Lucía
authors.initials: L
authors.lastname: Barrera
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alemán
authors.forename: Eduardo
authors.initials: E
authors.lastname: Abatte
authors.forename: María C
authors.initials: MC
authors.lastname: Sasiain
authors.forename: Silvia
authors.initials: S
authors.lastname: de la Barrera
mesh_terms: D001118:Argentina; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004196:Disease Outbreaks; D005434:Flow Cytometry; D006801:Humans; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*
chemical_list: D016207:Cytokines