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We previously reported that patients with multidrug‐resistant tuberculosis (MDR‐TB) showed low systemic and Mtb‐induced Th22 responses associated to high sputum bacillary load and severe lung lesions suggesting that Th22 response could influence the ability of these patients to control bacillary growth and tissue damage. In MDR‐TB patients, the percentage of IL‐22+ cells inversely correlates with the proportion of senescent PD‐1+ T cells. Herein, we aimed to evaluate the pathways involved on the regulation of systemic and Mtb‐induced Th22 response in MDR‐TB and fully drug‐susceptible TB patients (S‐TB) and healthy donors. Our results show that while IL‐1β and IL‐23 promote Mtb‐induced IL‐22 secretion and expansion of IL‐22+ cells, TGF‐β inhibits this response. Systemic and in vitro Mtb‐induced Th22 response inversely correlates with TGF‐β amounts in plasma and in PBMC cultures respectively. The number of circulating PD‐1+ T cells directly correlates with plasmatic TGF‐β levels and blockade of PD‐1/PD‐L1 signalling enhances in vitro Mtb‐induced expansion of IL‐22+ cells. Thus, TGF‐β could also inhibit Th22 response through upregulation of PD‐1 expression in T cells. Higher percentage of IL‐23+ monocytes was observed in TB patients. In contrast, the proportion of IL‐1β+ monocytes was lower in TB patients with bilateral lung cavities (BCC) compared to those patients with unilateral cavities (UCC). Interestingly, TB patients with BCC showed higher plasmatic and Mtb‐induced TGF‐β secretion than patients with UCC. Thus, high TGF‐β secretion and subtle differences in IL‐23 and IL‐1β expression could diminish systemic and in vitro Mtb‐induced Th22 response along disease progression in TB patients. [ABSTRACT FROM AUTHOR]

In human tuberculosis (TB), CD8+ T cells contribute to host defense by the release of Th1 cytokines and the direct killing of Mycobacterium tuberculosis (Mtb)-infected macrophages via granule exocytosis pathway or the engagement of receptors on target cells. Previously we demonstrated that strain M, the most prevalent multidrug-resistant (MDR) Mtb strain in Argentine, is a weak inducer of IFN-γ and elicits a remarkably low CD8-dependent cytotoxic T cell activity (CTL). In contrast, the closely related strain 410, which caused a unique case of MDR-TB, elicits a CTL response similar to H37Rv. In this work we extend our previous study investigating some parameters that can account for this discrepancy. We evaluated the expressions of the lytic molecules perforin, granzyme B and granulysin and the chemokine CCL5 in CD8+ T cells as well as activation markers CD69 and CD25 and IL-2 expression in CD4+ and CD8+ T cells stimulated with strains H37Rv, M and 410. Our results demonstrate that M-stimulated CD8+ T cells from purified protein derivative positive healthy donors show low intracellular expression of perforin, granzyme B, granulysin and CCL5 together with an impaired ability to form conjugates with autologous M-pulsed macrophages. Besides, M induces low CD69 and IL-2 expression in CD4+ and CD8+ T cells, being CD69 and IL-2 expression closely associated. Furthermore, IL-2 addition enhanced perforin and granulysin expression as well as the degranulation marker CD107 in M-stimulated CD8+ T cells, making no differences with cells stimulated with strains H37Rv or 410. Thus, our results highlight the role of IL-2 in M-induced CTL activity that drives the proper activation of CD8+ T cells as well as CD4+ T cells collaboration. [ABSTRACT FROM AUTHOR]

Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune responses but it is also associated with tissue-damaging inflammation. So, we evaluated the ability of Mycobacterium tuberculosis clinical isolates to induce IL-17 in tuberculosis (TB) patients and in healthy human tuberculin reactors (PPD+HD). Methods. IL-17, interferon c (IFN-c), and interleukin 23 (IL-23) receptor expression were evaluated ex vivo and cultured peripheral blood mononuclear cells from TB and PPD+HD stimulated with irradiated clinical isolates from multidrug resistant (MDR) outbreaksM(Haarlem family) and Ra (Latin American-Mediterranean family), as well as drug-susceptible isolates belonging to the same families and laboratory strain H37Rv for 48 hours in T-cell subsets by flow cytometry. Results. We observed that: (1) MDR strains M and Ra are stronger IL-17 inducers than drug-susceptible Mtb strains of the Haarlem and Latin American-Mediterranean families, (2) MDR-TB patients show the highest IL-17 expression that is independent on the strain, (3) IL-17 expression is dependent on CD4+ and CD8+ T-cells associates with persistently high antigen load. Conclusions. IL-17-producing T cells could play an immunopathological role in MDR-TB promoting severe tissue damage, which may be associated with the low effectiveness of the second-line drugs employed in the treatment. [ABSTRACT FROM AUTHOR]

During a chronic infection such as tuberculosis, the pool of tissue dendritic cells (DC) must be renewed by recruitment of both circulating DC progenitors and monocytes (Mo). However, the microenvironment of the inflammatory site affects Mo differentiation. As DC are critical for initiating a Mycobacterium tuberculosis-specific T-cell response, we argue that interference of M. tuberculosis with a correct DC generation would signify a mechanism of immune evasion. In this study, we showed that early interaction of γ-irradiated M. tuberculosis with Mo subverts DC differentiation in vitro. We found that irradiated M. tuberculosis effect involves (1) the loss of a significant fraction of monocyte population and (2) an altered differentiation process of the surviving monocyte subpopulation. Moreover, in the absence of irradiated M. tuberculosis, DC consist in a major DC-specific intercellular adhesion molecule 3-grabbing non-integrin receptor (DC-SIGNhigh)/CD86low and minor DC-SIGNlow/CD86high subpopulations, whereas in the presence of bacteria, there is an enrichment of DC-SIGNlow/CD86high population. Besides, this population enlarged by irradiated M. tuberculosis, which is characterized by a reduced CD1b expression, correlates with a reduced induction of specific T-lymphocyte proliferation. The loss of CD1molecules partially involves toll-like receptors (TLR-2)/p38 MAPK activation. Finally, several features of Mo, which have been differentiated into DC in the presence of irradiated M. tuberculosis, resemble the features of DC obtained from patients with active tuberculosis. In conclusion, we suggest that M. tuberculosis escapes from acquired immune response in tuberculosis may be caused by an altered differentiation into DC leading to a poor M. tuberculosis-specific T-cell response. [ABSTRACT FROM AUTHOR]