Expansion of Th17 and Th1-Th17 cells by outbreak multidrug-resistant clinical isolates of Mycobacterium tuberculosis.

DE LA BARRERA SILVIA

Buenos Aires

Workshop; 1st German-Argentinean Workshop on ?Pathogen Invasion and Immune Evasion?; 2012

Fundación Crimson

IL-17 is a pro-inflammatory cytokine that plays an important role in the development of autoimmunity, graft rejection and in the immune response against intracellular pathogens. Recent studies in animal models have demonstrated that IL-17 is essential for the development of a protective response in mycobacterial infections; however, it has also been associated with tissue-damaging inflammation. So, we evaluated the ability to induce IL-17 response in multidrug-resistant tuberculosis patients (MDR-TB) by Mycobacterium tuberculosis clinical isolates from Haarlem and Latin-American-Mediterranean lineages. We observed that outbreaks of Mycobacterium tuberculosis MDR strains M (Haarlem) and Ra (LAM) are stronger inducers of Th17 than drug-sensitive Mtb-strains of the same lineage. Besides, MDR-TB patients show a strong Th17 response that is dependent on CD4+ and CD8+ T cells and independent of the strain. Regarding to the cytokines involved in the expansion of memory Th17 cells, we observed that IL-1b, IL-23 and IL-6 are essential for the expansion on both IL-17+IFNg- and IL-17+IFNg+ subsets, while M and Ra-induced TGF-b directs Th17 response towards a single IL-17+IFNg- phenotype suggesting the plasticity of Th17 subsets to cytokine environment. On the other hand, blockade of IL-23p19 enhanced IL-17-IFN+ cells contributing to the impairment of Th1 response from MDR-TB. Interestingly, MDR-TB show an altered proportion of IL-17+IFNg- cells that associates with persistently high antigen load. Our results suggest that high Th17 response could have an immunopathological role that could contribute to the chronic and severe inflammatory process observed in MDR-TB.