Patients with multidrug resistant tuberculosis display impaired Th1 response and enhanced regulatory T cells levels in response to M and Ra outbreak multidrug resistant Mycobacterium tuberculosis strains

GEFFNER L; YOKOBORI N; BASILE J; SCHIERLOH P; BALBOA L; ROMERO MM; RITACCO V; VESCOVO M; GONZALEZ MONTANER P; LOPEZ B; BARRERA L; ALEMÁN M; ABATTE E; SASIAIN MC; DE LA BARRERA S

INFECTION AND IMMUNITY

AMER SOC MICROBIOLOGY

Lugar: Washington DC, USA; Año: 2009 vol. 77 p. 5025 - 5034

0019-9567

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- ) 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- 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.