title: Regulatory T cells attenuate mycobacterial stasis in alveolar and blood-derived macrophages from patients with tuberculosis.
abstract: BACKGROUND
  There are hardly any data about the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (T-Regs) in the lungs of patients with active tuberculosis (TB).
  
  
  OBJECTIVE
  To obtain data about the frequency of CD4(+)CD25(+)Foxp3(+) T-Regs, and their impact on mycobacterial containment, in the lungs of patients with active TB.
  
  
  METHODS
  Patients with pulmonary TB (n = 49) and healthy volunteers with presumed latent TB infection (LTBI; n = 38) donated blood and/or bronchoalveolar lavage (BAL) cells obtained by bronchoscopy. T-cell phenotype (Th1/Th2/Th17/T-Reg) and functional status was evaluated using flow-cytometry and (3)H-thymidine proliferation assays, respectively. H37Rv-infected alveolar and monocyte-derived macrophages were cocultured with autologous T-Regs and purified protein derivative (PPD) preprimed T-Reg-depleted effector cells. Mycobacterial containment was evaluated by counting CFUs.
  
  
  RESULTS
  In blood and BAL T-Reg levels were higher in TB versus LTBI (P < 0.04), and in TB the frequency of T-Regs was significantly higher in BAL versus blood (P < 0.001). T-Reg-mediated suppression of T-cell proliferation in blood and BAL was concentration-dependent. Restriction of mycobacterial growth in infected alveolar and monocyte-derived macrophages was significantly diminished, and by up to 50%, when T-Regs were cocultured with PPD-primed CD4(+) effector T cells. The levels of CD8(+) T-Regs (CD8(+)CD25(+)Foxp3(+)), IL-17-producing T-Regs (IL-17(+)CD4(+)CD25(+)Foxp3(+)), and IL-17-producing T cells were similar in BAL-TB versus BAL-LTBI. Within the TB group compartmentalization of responses was prominent (T-Reg, IFN-γ, tumor necrosis factor-α, IL-17, and IL-22 significantly higher in BAL vs. blood).
  
  
  CONCLUSIONS
  In patients with TB the alveolar compartment is enriched for CD4(+) T-Regs. Peripheral blood-derived T-Regs decrease the ability of alveolar and monocyte-derived macrophages to restrict the growth of Mycobacterium tuberculosis in the presence of effector cells. Collectively, these data suggest that CD4(+)CD25(+)FoxP3(+) T-Regs subvert antimycobacterial immunity in human TB.
authors.affiliation: Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Semple
authors.forename: Anke B
authors.initials: AB
authors.lastname: Binder
authors.forename: Malika
authors.initials: M
authors.lastname: Davids
authors.forename: Alice
authors.initials: A
authors.lastname: Maredza
authors.forename: Richard N
authors.initials: RN
authors.lastname: van Zyl-Smit
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000382:microbiology; D001999:Bronchoscopy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines