Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+IFNγ– CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis

• DOI: 10.1111/cei.12873
• Publication Date: 2016-09-28T14:33:11Z
• Authors: J I Basile; D Kviatcovsky; M M Romero; L Balboa; J Monteserin; V Ritacco; B Lopez; C Sabio y García; A García; M Vescovo; P G Montaner; D Palmero; M del Carmen Sasiain; S de la Barrera
• Keywords: Adult; Male; 0301 basic medicine; Multi-Drug-Resistance; Th17 Response; Interleukin-23; Mycobacterium; Interferon-gamma; Young Adult; 03 medical and health sciences; Species Specificity; https://purl.org/becyt/ford/3.3; Transforming Growth Factor beta; Drug Resistance, Multiple, Bacterial; Mdr; https://purl.org/becyt/ford/3.1; Tuberculosis, Multidrug-Resistant; Tuberculosis; Humans; https://purl.org/becyt/ford/3; Tuberculosis, Pulmonary; Cells, Cultured; Interleukin-17; Mycobacterium tuberculosis; Middle Aged; Toll-Like Receptor 2; 3. Good health; Cytokines; Th17 Cells; Female; Pattern Recognition Receptors; Immunologic Memory; Mycobacterium Tuberculosis; Signal Transduction

Summary We have reported previously that T cells from patients with multi-drug-resistant tuberculosis (MDR-TB) express high levels of interleukin (IL)-17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis (M. tuberculosis). Herein, we explore the pathways involved in the induction of Th17 cells in MDR-TB patients and healthy tuberculin reactors [purified protein derivative healthy donors (PPD+ HD)] by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17+interferon (IFN)-γ– and IL-17+IFN-γ+ in CD4+ T cells from MDR-TB and PPD+ HD. IL-23 plays an ambiguous role in T helper type 1 (Th1) and Th17 profiles: alone, IL-23 is responsible for M. tuberculosis-induced IL-17 and IFN-γ expression in CD4+ T cells from PPD+ HD whereas, together with transforming growth factor (TGF-β), it promotes IL-17+IFN-γ– expansion in MDR-TB. In fact, spontaneous and M. tuberculosis-induced TGF-β secretion is increased in cells from MDR-TB, the M strain being the highest inducer. Interestingly, Toll-like receptor (TLR)-2 signalling mediates the expansion of IL-17+IFN-γ– cells and the enhancement of latency-associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR-TB, which suggests that the M strain promotes IL-17+IFN-γ– T cells through a strong TLR-2-dependent TGF-β production by antigen-presenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR-TB patients infected with MDR Haarlem strains show higher IL-17+IFN-γ– and lower IL-17+IFN-γ+ levels than LAM-infected patients. The present findings deepen our understanding of the role of IL-17 in MDR-TB and highlight the influence of the genetic background of the infecting M. tuberculosis strain on the ex-vivo Th17 response.