Modulation of human dendritic cells funtional activity by M. tuberculosis

Mycobacterium tuberculosis (Mtb) subverts the functional activity of dendritic cells (DC) and influences T cell-mediated immune responses. Here we show that Mtb alters monocytes differentiation into DC with formation of CD14+ cells showing decreased CD1a and CD1c acquisition and producing TNF-α, little amounts of IL-1β, IL-6, IL-23 and no IL-12. These cells are unable to induce substantial IFN-γ or IL-17 production in CD4+ lymphocytes. The treatment of conventionally differentiated monocyte-derived DC with Mtb elicits the formation of mature DC producing high amounts of IL-1β, IL-6, IL-23 and TNF-α, stimulating the secretion of IFN-γ and IL-17 by CD4+ lymphocytes. Here we also show that TNF-α, IL-1β, IL-23, and IL-6 secretion is mainly due to dectin-1 receptor engagement by Mtb, whereas TLR2 does not play an essential role in the release of these cytokines. Accordingly, DC stimulation with the dectin-1 agonist glucan triggers Th1/Th17 polarization independently of TLR2 engagement. These findings indicate that dectin-1 could be the most important receptor involved in induction of Th1/Th17 generation. Here we also report that DC-SIGN or CD206 engagement leads to a decrease of Mtb-dependent TNF-α, IL-1β, IL-23, and IL-6 production by DC. These effects are probably due to an interference of CD206 and DC-SIGN on dectin-1-activated signals, as suggested by the experiments performed with soluble receptor agonists, in which simultaneous addition of the specific dectin-1 agonist and CD206 or DC-SIGN ligands results in depressed cytokine release. Moreover, some soluble secreted antigens from Mtb have been tested. Among them, HspX gave the most interesting results. In fact, it significantly decreased IL-23 and increased TNF-α, IL-1β, IL-6 secretion by DC in response to Mtb. We also found that HspX switched Mtb-dependent Th1/Th17 polarization towards the Th1 response, with decreased IL-17 and enhanced IFN-γ production by CD4+ T cells, probably as a consequence of the above-mentioned changes of cytokine expression. Interestingly, HspX treatment during the Mtb-induced maturation process increased CD206 and DC-SIGN, and decreased dectin-1 expression as compared to Mtb-matured DC. These results suggest that antigen HspX could limit the receptor arrangements induced by the direct contacts between Mtb and DC. Our results indicate that Mtb could modulates the functional polarization of T lymphocytes by affecting DC differentiation and cytokine release through mechanisms involving interactions of the pathogen with dectin-1, DC-SIGN and CD206.