Toll-Like Receptor 2-Dependent Inhibition of Macrophage Class II MHC Expression and Antigen Processing by 19-kDa Lipoprotein ofMycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (MTB) induces vigorous immune responses, yet persists inside macrophages, evading host immunity. MTB bacilli or lysate was found to inhibit macrophage expression of class II MHC (MHC-II) molecules and MHC-II Ag processing. This report characterizes and identifies a specific component of MTB that mediates these inhibitory effects. The inhibitor was extracted from MTB lysate with Triton X-114, isolated by gel electroelution, and identified with Abs to be MTB 19-kDa lipoprotein. Electroelution- or immunoaffinity-purified MTB 19-kDa lipoprotein inhibited MHC-II expression and processing of both soluble Ags and Ag 85B from intact MTB bacilli. Inhibition of MHC-II Ag processing by either MTB bacilli or purified MTB 19-kDa lipoprotein was dependent on Toll-like receptor (TLR) 2 and independent of TLR 4. Synthetic analogs of lipopeptides from Treponema pallidum also inhibited Ag processing. Despite the ability of MTB 19-kDa lipoprotein to activate microbicidal and innate immune functions early in infection, TLR 2-dependent inhibition of MHC-II expression and Ag processing by MTB 19-kDa lipoprotein during later phases of macrophage infection may prevent presentation of MTB Ags and decrease recognition by T cells. This mechanism may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

Recombinant MPT83 Derived fromMycobacterium tuberculosisInduces Cytokine Production and Upregulates the Function of Mouse Macrophages through TLR2

“…In addition to the classical function of MHC-II molecules in presenting Ag to CD4 + T cells, MHC-II molecules can activate various cellular functions in immune or nonimmune cells when cross-linked by Ab or superantigen (75)(76)(77)(78). Previous studies showed that prolonged TLR2 signaling by mycobacterial lipoproteins, such as 19-kDa lipoprotein, inhibits MHC-II expression and Ag processing in macrophages (20,22). In our studies, prolonged TLR2 signaling by rMPT83 enhanced MHC-II expression and Ag presentation by macrophages.…”

“…The survival of M. tuberculosis may be associated with an inhibition of IFNg-dependent responses. Prolonged (.18 h) infection of macrophages with M. tuberculosis or exposure to lipoarabinomannan, 19-kDa lipoprotein, LprG, or LprA inhibits the IFN-g-induced expression of certain genes (20)(21)(22)(23)(24). M. tuberculosis also inhibits macrophage expression of CIITA and genes that are regulated by CIITA, including MHC-II, H2-M, and invariant chain (40).…”

“…In mice, TLR2 deficiency increases susceptibility to M. tuberculosis infection (15,16). Several mycobacterial ligands for TLR2 have been identified, including lipomannan (17), lipoarabinomannan (18,19), and the lipoproteins LpqH (19 kDa; Rv3763) (20)(21)(22), LprG (Rv1411c) (23), LprA (24), MPB83 (25), and a 38-kDa lipoprotein (26).…”

LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest

“…TLR2 contributes to innate resistance against M. tuberculosis (Reiling et al, 2002). In vitro investigations suggest that the triggering of TLR2 by M. tuberculosis may represent a double-edged sword: shortterm signalling through TLR2 activates macrophages and initiates inflammation via TNF-a secretion that may help to control the acute infection (Underhill et al, 1999); prolonged TLR2 signalling in macrophages results in downregulation of major histocompatibility complex (MHC)-II antigen processing, suppressing an acquired immune response (Gehring et al, 2004;Noss et al, 2001). The link between TLR2 triggering and phagosome maturation is controversial: Blander & Medzhitov (2004) reported that TLR stimulation promotes phagosome maturation, while provided evidence that TLR2 or TLR4 stimulation does not affect phagosome acidification or phago-lysosomal fusion.…”

Virulence Factors and Pathogenicity of Mycobacterium

“…LpqH is recognized by the immune system and induces T cell proliferation in vitro, stimulates DC maturation and autophagy and activates TLR-2 [67]. The protein alters the expression and presentation of antigens by MHCII [68]. 19kDa protein, induces macrophage apoptosis by caspase-dependent and -independent mechanisms with activation of the initiator caspase 8 and executioner caspase 3 [69].…”