title: Recombinant Lipoprotein Rv1016c Derived fromMycobacterium tuberculosisIs a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing.
abstract: TLR2-dependent cellular signaling inMycobacterium 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.
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Joint of School of Life Science, Guangzhou Medical UniversityGuangzhou, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhou, China; State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan UniversityShanghai, China; Department of Clinical Laboratory, Second People's Hospital of Guangdong ProvinceGuangzhou, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Su
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University Shanghai, China.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: CAS Key Laboratory of Regenerative Biology, Joint of School of Life Science, Guangzhou Medical UniversityGuangzhou, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University Shanghai, China.
authors.forename: Honghai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Second People's Hospital of Guangdong Province Guangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002473:Cell Wall / Q000737:chemistry; D004269:DNA, Bacterial; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005798:Genes, Bacterial / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020102:Mycobacterium smegmatis; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000145:classification / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D000949:Histocompatibility Antigens Class II; D008074:Lipoproteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015534:Trans-Activators; D007371:Interferon-gamma
keywords: MHC II; Mycobacterium tuberculosis; Rv1061c; TLR2; apoptosis