Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Abstract

TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2−/− mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…176 It is worth mentioning that immune evasion via modulation of TLR2 by the recombinant lipoprotein Rv1016c, induces apoptosis of macrophages by increasing annexin expression. 177 Consequently, this relationship becomes beneficial because in addition to Rv1016c inhibition of MHC-II expression, TLR2-dependent apoptosis may promote the release of residual bacilli into apoptotic cells and, thereby, decrease the recognition of CD4+ T cells, impairing surveillance in chronic disease conditions (Figure 3). 177 Concerning protozoa, one of the main parasites that compromise macrophage activity is Leishmania.…”

“…177 Consequently, this relationship becomes beneficial because in addition to Rv1016c inhibition of MHC-II expression, TLR2-dependent apoptosis may promote the release of residual bacilli into apoptotic cells and, thereby, decrease the recognition of CD4+ T cells, impairing surveillance in chronic disease conditions (Figure 3). 177 Concerning protozoa, one of the main parasites that compromise macrophage activity is Leishmania. 163 L. major negatively modulates TLR2 receptor activity to increase the recruitment of SOCS1 and SOCS3, which inhibit the production of NF-kB, IFN-γ, and TNF-α in order to establish pathogen survival.…”

Intelligent Mechanisms of Macrophage Apoptosis Subversion by Mycobacterium

“…LpqT could decrease the cleaved levels of caspase-3 by blocking the TLR-2 signaling pathway (Table 1) [39]. However, the previous study demonstrated that LpqT could increase the apoptosis of THP-1 macrophage and monocyte-derived macrophages (MDM) via agonist TLR-2 signaling [40]. Therefore, the exact role of Mtb LpqT in the regulation of macrophage apoptosis in the context of its interaction with TLR-2 remains controversial.…”

March of Mycobacterium: miRNAs intercept host cell CD40 signalling

“…TLR2-Mtb lipoprotein interaction inhibits IFN-c-induced MHC-II expression and processing of soluble antigens in a Class II transactivator (CIITA) IVdependent and MAPK-dependent manner. 110 Repressed MHC-II expression and enhanced TLR2driven macrophage apoptosis decrease antigen recognition by CD4 + T cells. IL-10 plays a significant role in this process.…”