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.
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.
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
J I
JI
Basile
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
D
D
Kviatcovsky
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
M M
MM
Romero
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
L
L
Balboa
Instituto Nacional de Enfermedades Infecciosas, ANLIS Carlos G. Malbrán, Buenos Aires, Argentina.
J
J
Monteserin
Instituto Nacional de Enfermedades Infecciosas, ANLIS Carlos G. Malbrán, Buenos Aires, Argentina.
V
V
Ritacco
Instituto Nacional de Enfermedades Infecciosas, ANLIS Carlos G. Malbrán, Buenos Aires, Argentina.
B
B
Lopez
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
C
C
Sabio y García
Instituto de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina.
A
A
García
Instituto de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina.
M
M
Vescovo
Instituto de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina.
P G
PG
Montaner
Instituto de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina.
D
D
Palmero
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
M
M
Del Carmen Sasiain
Instituto de Medicina Experimental-CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
S
S
de la Barrera
D000328:Adult; D002478:Cells, Cultured; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013045:Species Specificity; D058504:Th17 Cells / Q000276:immunology* / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018088:Tuberculosis, Multidrug-Resistant / Q000235:genetics / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology; D055815:Young Adult
D020381:Interleukin-17; D053759:Interleukin-23; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma
Mycobacterium tuberculosis; Th17 cells; cytokines; multi-drug-resistance; pattern recognition receptors
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