Immunological hyporesponsiveness in tuberculosis: The role of mycobacterial glycolipids

Abstract

Glycolipids constitute a major part of the cell envelope of Mycobacterium tuberculosis (Mtb). They are potent immunomodulatory molecules recognized by several immune receptors like pattern recognition receptors such as TLR2, DC-SIGN and Dectin-2 on antigen-presenting cells and by T cell receptors on T lymphocytes. The Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic relatives, phosphatidylinositol mannosides (PIMs) and lipomannan (LM), as well as other Mtb glycolipids, such as phenolic glycolipids and sulfoglycolipids have the ability to modulate the immune response, stimulating or inhibiting a pro-inflammatory response. We explore here the downmodulating effect of Mtb glycolipids. A great proportion of the studies used in vitro approaches although in vivo infection with Mtb might also lead to a dampening of myeloid cell and T cell responses to Mtb glycolipids. This dampened response has been explored ex vivo with immune cells from peripheral blood from Mtb-infected individuals and in mouse models of infection. In addition to the dampening of the immune response caused by Mtb glycolipids, we discuss the hyporesponse to Mtb glycolipids caused by prolonged Mtb infection and/or exposure to Mtb antigens. Hyporesponse to LAM has been observed in myeloid cells from individuals with active and latent tuberculosis (TB). For some myeloid subsets, this effect is stronger in latent versus active TB. Since the immune response in individuals with latent TB represents a more protective profile compared to the one in patients with active TB, this suggests that downmodulation of myeloid cell functions by Mtb glycolipids may be beneficial for the host and protect against active TB disease. The mechanisms of this downmodulation, including tolerance through epigenetic modifications, are only partly explored.

Keywords: Mycobacterium; glycolipid; immunological tolerance; latency; lipoarabinomannan; tuberculosis.

Figure 1

Mycobacterial glycolipids are associated with immune hyporesponse in distinct circumstances. Concurrent exposure – referred as the hyporesponse to distinct stimuli due to concurrent exposure to mycobacterial glycolipids. Previous exposure - represents the hyporesponse to glycolipids or other stimuli due to previous, repeated or continuous exposure to diverse Mtb antigens.

Figure 2

Schematic representation of the Mycobacterium tuberculosis cell envelope. AG, arabinogalactan; DAT, di-acyltrehalose; GMM, glucose monomycolate; GroMM, glycerol monomycolate; LAM, lipoarabinomannan; LM, lipomannan; PAT, penta-acyltrehalose; PIM, phosphatidylinositol mannoside; PDIM, phthiocerol dimycocerosate; PGL, phenolic glycolipid; SGL, sulfoglycolipid; TAT, tetra-acyltrehalose; TDM, trehalose-6,6’-dimycolate; TMM, trehalose monomycolate.

Figure 3

Some of the signaling pathways in the context of hyporesponsiveness in monocytes/macrophages and DCs. The TLR signaling pathways induced by PAMPs, such as LPS and Mtb glycolipids activate NF-κB and MAPK cascades in macrophages and DCs, leading to the production of pro-inflammatory cytokines. Most TLRs bind the adaptor protein MyD88, initiating signaling through the serine/threonine kinase IRAK, which then associates with the adaptor protein TRAF6. After the activation of the IKK complex, IκB, an inhibitor of NF-κB, becomes phosphorylated and then degraded. This leads to the activation of NF-κB and its translocation to the nucleus with subsequent production of immunostimulatory cytokines and DC maturation. Interaction with DC-SIGN, which is mainly expressed on the surface of DCs, activates the small GTPase, Ras, leading to the activation of NF-κB by phosphorylation of the p65 subunit at Ser276 and its subsequent acetylation, thereby enhancing the production of the immunosuppressive cytokine IL-10 (44, 76, 99, 100). The negative regulator of TLR signaling, IRAK-M, is induced in macrophages and DCs in response to the first activation of the TLRs and functions as a negative regulator in the second or continuous stimulation by TLR agonists. The IRAK family includes two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M inhibits further downstream activation of NF-κB by preventing the dissociation of IRAK and IRAK-4 from MyD88 and the formation of IRAK-TRAF6 complexes (101). Another negative regulator of TLR signaling is PI3K, which is constitutively expressed in innate immune cells, such as DCs and macrophages. Unlike IRAK-M, PI3K functions at the early phase of TLR signaling in response to the first encounter with the pathogens. PI3K activates AKT (also known as PKB), which inhibits both NF-κB and the MAPK pathway, leading to reduced inflammatory cytokine production (102). In addition to the activation of NF-κB, TLR ligation also activates the MAPK pathway. MK2, is a kinase that is downstream of p38 and regulates the synthesis of pro-inflammatory cytokines. Downmodulation of MK2 therefore results in reduced cytokine production. TLR4 ligation can in addition to MyD88 also signal via TRIF to IRF3 leading to production of type 1 IFNs (103). DCs, dendritic cells; TLR, Toll-like receptor; PAMP, pathogen associated molecular patterns; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; IRAK, iIL-1 receptor-associated kinase; TRAF6, TNF-receptor-associated factor 6; IKK, inhibitor of NF-κB kinase; LAM, lipoarabinomannan; DC-SIGN, DC-specific intracellular adhesion molecule-grabbing non- integrin; IRAK-M, IL-1 associated kinase-M; PGL, phenolic glycolipid; SGL, sulfoglycolipid.

Figure 4

Schematic presentation of induction of innate training vs tolerance. (A) Innate training or tolerance can be achieved in vitro by using different times of primary stimulation and resting of immune cells, different concentrations of the stimuli, and different secondary stimuli. (B) In vivo innate training and tolerance can potentially be achieved by infection (primary stimulation) for varying times and doses and expressed ex vivo upon secondary stimulation of immune cells from the infected individual.