title: Brucella abortusdown-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1).
abstract: Brucella abortusis an intracellular pathogen capable of surviving inside of macrophages. The success ofB. abortusas a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4+T cell responses that it elicits. Previously, we demonstrated thatB. abortusinhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, wherebyB. abortusis able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated thatB. abortusinfection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished.B. abortuswas not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypicalB. abortuslipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent asB. abortusinfection. IL-6 contributes to these down-regulatory phenomena. In addition,B. abortusand its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet,B. abortuslipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate thatB. abortusinhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection.
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Lis N
authors.initials: LN
authors.lastname: Velásquez
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: M Ayelén
authors.initials: MA
authors.lastname: Milillo
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Delpino
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Aldana
authors.initials: A
authors.lastname: Trotta
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernández
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Roberto G
authors.initials: RG
authors.lastname: Pozner
authors.affiliation: Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Freidrich Alexander Universität Erlangen-Nürnberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Balboa
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; and.
authors.forename: Guillermo H
authors.initials: GH
authors.lastname: Giambartolomei
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas-Academia Nacional de Medicina, Buenos Aires, Argentina; pbarrion2004@yahoo.com.ar.
authors.forename: Paula
authors.initials: P
authors.lastname: Barrionuevo
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D002003:Brucella abortus / Q000502:physiology*; D002006:Brucellosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000382:microbiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; D008074:Lipoproteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C097319:OMP19 protein, Brucella abortus; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D015534:Trans-Activators; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S
keywords: bacteria; host immunity; immune-evasion strategies; monocytes/macrophages