ABSTRACT
The expansion of CD4+ CD25+ forkhead box (FOX)P3+ regulatory T (Treg) cells has been observed in patients with Mycobacterium (M.) tuberculosis; however, the mechanism of expansion remains to be elucidated. The aim of the present study was to examine the role of the early secreted antigenic target 6(ESAT6) and antigen 85 complex B (Ag85B) from M. tuberculosis on Treg cell expansion. To investigate the sensitivity of peripheral blood cultures to the M. tuberculosis ESAT6 and Ag85B antigens, the proportion of circulating CD4+ CD25+ FOXP3+ Treg cells was determined using flow cytometry and the levels of FOXP3 mRNA were determined using reverse transcription quantitative polymerase chain reaction. The mRNA levels of FOXP3 and the proportion of circulating CD4+ CD25+ FOXP3+ Treg cells were increased in multiplicitous drugresistant tuberculosis patients compared with those in healthy controls and patients with latent tuberculosis (TB) infection (LTBI) (P<0.001). The mycobacterial antigens ESAT6 and Ag85B increased the expansion of the CD4+ CD25+ FOXP3+ Treg cells and the mRNA levels of FOXP3 in healthy controls and LTBI patients compared with the effect of Bacillus CalmetteGuerin (P<0.05). Additionally, the mRNA levels of FOXP3 were elevated in the LTBI patients following stimulations with the mycobacterial antigens (P=0.012). Therefore, the M. tuberculosis antigens ESAT6 and Ag85B induced CD4+ CD25+ FOXP3+ Tregcell expansion, particularly in patients with LTBI. These findings indicated that CD4+ CD25+ FOXP3+ Treg cells may have a primary role in the failure of the host immune system to eradicate M. tuberculosis.
Subject(s)
Acyltransferases/immunology , Antigens, Bacterial/immunology , Bacterial Proteins/immunology , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Tuberculosis/immunology , Adolescent , Adult , Aged , CD4 Lymphocyte Count , Case-Control Studies , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression , Humans , Immunophenotyping , Latent Tuberculosis/genetics , Latent Tuberculosis/immunology , Male , Middle Aged , Mycobacterium tuberculosis/drug effects , Phenotype , RNA, Messenger/genetics , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/genetics , Tuberculosis, Multidrug-Resistant/genetics , Tuberculosis, Multidrug-Resistant/immunology , Young AdultABSTRACT
OBJECTIVES: Immune regulatory mechanisms may limit the immunopathologic condition of infection with Mycobacterium tuberculosis and suppress cellular immune responses in the host. We investigated the CD4(+)CD25(+)FoxP3(+) circulating regulatory T cells (T(reg)) in patients with cavity multidrug-resistant tuberculosis (MDR-TB) before and after surgery. METHODS: We compared the proportion of T(reg) cells in 13 patients with cavity MDR-TB pre- and postoperatively and in 10 healthy control subjects by flow cytometry using three specific markers in peripheral blood lymphocytes: cell-surface CD4 and CD25 expression and intracellular FoxP3 expression. RESULTS: The proportion of CD4(+)CD25(high) and CD4(+)CD25(+)FoxP3(+) T(reg) was significantly higher in patients with cavity MDR-TB and at 1-month postoperatively than in healthy controls (p<0.001). The proportion of CD4(+) and CD4(+)CD25(-) cells was significantly lower in patients with cavity MDR-TB than in controls (p<0.001). Pre- and postoperative proportions of CD4(+)CD25(high) and CD4(+)CD25(+)FoxP3(+) T(reg) cells showed a positive correlation (r=0.878, p<0.001). CONCLUSION: Circulating T(reg) cells are increased in proportion in patients with cavity MDR-TB and decreased after surgery. Infection with M. tuberculosis may induce T(reg) cell-surface molecular changes with increased numbers of cells.
