IL-17 and IFN-γ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease

Abstract

Th1 lymphocytes are crucial in the immune response against Mycobacterium tuberculosis. Nevertheless, IFN-␥ alone is not sufficient in the complete eradication of the bacteria, suggesting that other cytokines might be required for pathogen removal. Th17 cells have been associated with M. tuberculosis infection, but the role of IL-17-producing cells in human TB remains to be understood. Therefore, we investigated the induction and regulation of IFN-␥ and IL-17 during the active disease. TB patients were classified as High and Low Responder individuals according to their T cell responses against the antigen, and cytokine expression upon M. tuberculosis stimulation was investigated in peripheral blood and pleural fluid. Afterwards, the potential correlation among the proportions of cytokine-producing cells and clinical parameters was analyzed. In TB patients, M. tuberculosis induced IFN-␥ and IL-17, but in comparison with BCG-vaccinated healthy donors, IFN-␥ results were reduced significantly, and IL-17 was markedly augmented. Moreover, the main source of IL-17 was represented by CD4 ϩ IFN-␥ ϩ IL-17 ϩ lymphocytes, a Th1/Th17 subset regulated by IFN-␥. Interestingly, the ratio of antigen-expanded CD4 ϩ IFN-␥ ϩ IL-17 ϩ lymphocytes, in peripheral blood and pleural fluid from TB patients, was correlated directly with clinical parameters associated with disease severity. Indeed, the highest proportion of CD4 ϩ IFN-␥ ϩ IL-17 ϩ cells was detected in Low Responder TB patients, individuals displaying se-vere pulmonary lesions, and longest length of disease evolution. Taken together, the present findings suggest that analysis of the expansion of CD4 ϩ IFN-␥ ϩ IL-17 ϩ T lymphocytes in peripheral blood of TB patients might be used as an indicator of the clinical outcome in active TB.

Specific Recognition of Mycobacterial Protein and Peptide Antigens by γδ T Cell Subsets following Infection with VirulentMycobacterium bovis

“…We further show that significant numbers of bovine gd T cells produce and secrete IL-17 in response to stimulation with Mycobacterium; however, in contrast to reports from mice, the dominant producers of IL-17A protein are CD4 T cells during virulent M. bovis infection in cattle. Our result is particularly interesting, given that the primary source of IL-17 in human TB patients remains controversial (35)(36)(37). Together, our results suggest that multiple functional subsets of gd T cells respond to mycobacterial Ags in both the peripheral blood and tissues of M. bovis-infected animals, and they indicate a critical role for gd T cell subsets in the immune response to TB.…”

“…In mice, although there is a minor contribution by IL-17 + CD4 T cells, the Mycobacteriumspecific IL-17 response appears to be dominated by gd T cells (64,65). In humans with active TB, the result is less clear, with some reports citing dominant IL-17 production by gd T cells (37) and others citing CD4 T cells (35,36).…”

“…However, accumulating evidence also suggests the importance of additional inflammatory cytokines, particularly IL-17, as M. tuberculosis and BCG induce significant IL-17 responses in both mice and humans (36,(63)(64)(65). In mice, although there is a minor contribution by IL-17 + CD4 T cells, the Mycobacteriumspecific IL-17 response appears to be dominated by gd T cells (64,65).…”

TB/HIV pleurisy reduces Th17 lymphocyte proportion independent of the cytokine microenvironment

“…MTB cell wall component, trehalose-6-6'-dimycolate (TDM/cord factor) has been shown to induce the production of Th17 differentiating cytokines from antigen presenting cells through a the C-type lectin Mincle pathway [4]. Conflicting studies have noted an expansion of Th17/IL-17 axis in the peripheral blood and pleural fluid [5,6] and a reduced frequency of Th17 cells in peripheral blood [7,8] and bronchoalveolar lavage (BAL) fluid [7] during active MTB infection, with correlation to disease severity [5].…”

Investigation of microRNA expression and DNA repair gene transcripts in human oocytes and blastocysts

“…Recent studies proposed that more than half of the human transcriptome is regulated by microRNAs (miRNAs) [2,3]. Several miRNAs have been shown to regulate and be regulated by genes functioning at cell cycle checkpoints [4][5][6][7][8][9][10] and in different repair mechanisms: nucleotide excision repair [11], mismatch repair [12][13][14][15] and double-strand break repair [16][17][18][19][20][21] in cancer cells and cell lines.…”