Divergent Effects of Mycobacterial Cell Wall Glycolipids on Maturation and Function of Human Monocyte-Derived Dendritic Cells

Abstract

Background Mycobacterium tuberculosis (Mtb) is able to evade the immune defenses and may persist for years, decades and even lifelong in the infected host. Mtb cell wall components may contribute to such persistence by modulating several pivotal types of immune cells. Dendritic cells (DCs) are the most potent antigen-presenting cells and hence play a crucial role in the initial immune response to infections by connecting the innate with the adaptive immune system.Principal FindingsWe investigated the effects of two of the major mycobacterial cell wall-associated types of glycolipids, mannose-capped lipoarabinomannan (ManLAM) and phosphatidylinositol mannosides (PIMs) purified from the Mtb strains H37Rv and Mycobacterium bovis, on the maturation and cytokine profiles of immature human monocyte-derived DCs. ManLAM from Mtb H37Rv stimulated the release of pro-inflammatory cytokines TNF, IL-12, and IL-6 and expression of co-stimulatory (CD80, CD86) and antigen-presenting molecules (MHC class II). ManLAM from M. bovis also induced TNF, IL-12 and IL-6 but at significantly lower levels. Importantly, while ManLAM was found to augment LPS-induced DC maturation and pro-inflammatory cytokine production, addition of PIMs from both Mtb H37Rv and M. bovis strongly reduced this stimulatory effect.ConclusionsThese results indicate that the mycobacterial cell wall contains macromolecules of glycolipid nature which are able to induce strong and divergent effects on human DCs; i.e while ManLAM is immune-stimulatory, PIMs act as powerful inhibitors of DC cytokine responses. Thus PIMs may be important Mtb-associated virulence factors contributing to the pathogenesis of tuberculosis disease. These findings may also aid in the understanding of some earlier conflicting reports on the immunomodulatory effects exerted by different ManLAM preparations.

Lipoarabinomannan, and its related glycolipids, induce divergent and opposing immune responses to Mycobacterium tuberculosis depending on structural diversity and experimental variations

“…The interaction of ManLAM with DCs, in particular with human DCs, is less well studied than the interaction with M4s [61e63]. It was demonstrated that a highly purified H37Rv ManLAM was a potent activator of human DCs showing several similarities with LPS in respect to DC cytokine production and cell maturation profile [18] (Table 2). These observations are in agreement with the findings by Dulphy et al [64] where DCs were activated with ManLAM from H37Rv, displaying a dose-dependent maturation phenotype, in terms of CD83 and CD86 expression but in contrast to the findings by Geijtenbeek et al [63] and Wu et al [65] where ManLAM did not induce DC maturation.…”

“…ManLAM from H37Rv was shown to induce a strong proinflammatory cytokine response in human DCs, manifested by TNF, IL-6, and IL-12 release [18] (Table 1). Similar results were reported in a recent study using mouse cells, where ManLAM activated bone-marrow-derived DC were shown to produce pro-and anti-inflammatory cytokines via a C-type lectin receptor, Dectin-2 [66].…”

“…A deep analysis of the literature revealed that several factors contribute to such diverse effects and also to the lack of consistency. On one hand there are very important differences between the immunomodulatory abilities of the different glycolipids (PIM, LM, LAM and ManLAM and potentially others) present in the Mtb cell wall [18]; the analysis of the different molecules separately is essential if one aims to understand how Mtb glycolips modulate the host immune response. On the other hand, the same glycolipid may vary in composition between distinct Mtb complex strains.…”

“…these cells (which impact on the activation/maturation status of the cells, receptor (PPR) equipment and signalling pathways that are active). To all of these variables in the protocols used by distinct laboratories one needs still to consider the use of preparations of allegedly pure specific glycolipids that have been shown to be contaminated with other glycolipids or even other components [18].…”

Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids

“…Although synthetic Pim2 and Pim4 were able to bind TLR2, they were not able to support TNF-α secretion from C57BL/6 mice[10]. Pims also have been shown to inhibit the activation of TLR2 in a CD14 independent way [68], decrease allergic response [69–70] and affect dendritic cell maturation [71]. Lipoarabinomannan and phosphatidylinositol mannosides were reported to be sensed by TLR1 and TLR2[41].…”