title: Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients.
abstract: Previous studies have demonstrated that cells from both multi-drug-resistant tuberculosis (MDR-TB) and non-tuberculous mycobacteria (NTM) patients respond poorly to mycobacterial antigens in vitro. In the present study, we compared the in vitro response of cells isolated from sensitive TB (NR-TB)-, MDR-TB- and NTM-infected patients. Analysis of T cell phenotype ex vivo revealed that both MDR-TB and NTM patients present an increased percentage of CD4(+) CD25(+-)  forkhead box protein 3 (FoxP3)(+)  and CD4(+) CD25(+) CD127(-)  regulatory T (T(reg) ) cells when compared to NR-TB. Increased numbers of T(reg)  cells and interleukin (IL)-10 serum levels were detected in MDR-TB, whereas elevated serum transforming growth factor (TGF)-β was found in the NTM group. Cells of MDR-TB patients stimulated with early secretory antigenic target (ESAT)-6, but not purified protein derivative (PPD), showed a lower frequency of CD4(+) /interferon (IFN)-γ(+)  T cells and enhanced CD4(+) CD25(+) FoxP3(+) , CD4(+) CD25(+) CD127(-)  and CD4(+) CD25(+) IL-10(+)  T cell population. In addition, increased IL-10 secretion was observed in cultured MDR-TB cells following ESAT-6 stimulation, but not in NR-TB or NTM patients. In vitro blockade of IL-10 or IL-10Rα decreased the CD4(+) CD25(+) FoxP3(+)  frequencies induced by ESAT-6 in MDR-TB, suggesting a role of IL-10 on impaired IFN-γ responses seen in MDR-TB. Depletion of CD4(+) CD25(+)  T lymphocytes restored the capacity of MDR-TB T cells to respond to ESAT-6 in vitro, which suggests a potential role for T(reg) /T regulatory 1 cells in the pathogenesis of MDR-TB. Together, our results indicate that although the similarities in chronicity, NTM- and MDR-TB-impaired antigenic responses involve different mechanisms.
authors.affiliation: Leprosy Laboratory, Instituto Oswaldo Cruz, Oswaldo Cruz Foundation, Fiocruz, Brazil.
authors.forename: R O
authors.initials: RO
authors.lastname: Pinheiro
authors.forename: E B
authors.initials: EB
authors.lastname: de Oliveira
authors.forename: G
authors.initials: G
authors.lastname: Dos Santos
authors.forename: G M
authors.initials: GM
authors.lastname: Sperandio da Silva
authors.forename: B J
authors.initials: BJ
authors.lastname: de Andrade Silva
authors.forename: R M B
authors.initials: RM
authors.lastname: Teles
authors.forename: A
authors.initials: A
authors.lastname: Milagres
authors.forename: E N
authors.initials: EN
authors.lastname: Sarno
authors.forename: M P
authors.initials: MP
authors.lastname: Dalcolmo
authors.forename: E P
authors.initials: EP
authors.lastname: Sampaio
mesh_terms: D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018088:Tuberculosis, Multidrug-Resistant / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007538:Isoniazid; D012293:Rifampin