Dichotomy of cytokine profiles in patients and high-risk healthy subjects exposed to tuberculosis

Abstract

To better understand the role of cytokines in susceptible and resistant subjects exposed to Mycobacterium tuberculosis infection, intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) in ex vivo peripheral blood- derived CD4+ T cells were examined by flow cytometry. Of the 37 individuals examined, 20 had clinical evidence of pulmonary tuberculosis and showed acid- fast bacilli in the sputum. Other individuals in close contact with these patients showed no evidence of disease. Patients had a higher number of CD4+ T cells expressing IFN-γ and IL-4 in unstimulated cultures compared to healthy subjects. Despite this, the ratio of IFN-γ+ to IL-4+ CD4+ T cells was similar in both groups. The Th1 response seen in CD4+ T cells in patients was also observed in the overall pattern of IFN-γ, and IL-4 detected in control culture supernatants by enzyme-linked immunosorbent assay (ELISA). However, after in vitro stimulation of PBMC with heat-killed M. tuberculosis there was a significant reduction in the percentage of IFN-γ+ CD4+ T cells (P < 0.001) in patients. This trend was reflected in the IFN-γ ELISA assay with supernatants derived from stimulated cultures. However, the accumulated levels of IFN-γ were higher than those for IL-4. The reduction of IFN-γ+ CD4+ T cells resulted in the dominance of IL-4+ CD4+ T cells in 13 patients (P < 0.05). The elevated levels of IL-4+ CD4+ T cells seen in patients may contribute to the downregulation of IFN-γ expression and the crucial effector function of CD4 T cells, leading to the persistence of disease and the immunopathology characteristically seen in patients. Preliminary data on the indicators of apoptosis in antigen-stimulated cultures in PBMC derived from patients are presented. Of the 17 high-risk healthy individuals examined, 11 differed in that, after mycobacterial- antigen stimulation, there was an enhancement in IFN-γ+ CD4+ T cells.