title: Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide.
abstract: Pathogen-associated molecular patterns (PAMPs) signal through Toll-like receptors (TLRs) to activate immune responses, but prolonged exposure to PAMPs from Mycobacterium tuberculosis (MTB) and other pathogens inhibits class II MHC (MHC-II) expression and Ag processing, which may allow MTB to evade CD4(+) T cell immunity. Alternate class I MHC (MHC-I) processing allows macrophages to present Ags from MTB and other bacteria to CD8(+) T cells, but the effect of PAMPs on this processing pathway is unknown. In our studies, MTB and TLR-signaling PAMPs, MTB 19-kDa lipoprotein, CpG DNA, and LPS, inhibited alternate MHC-I processing of latex-conjugated Ag by IFN-gamma-activated macrophages. Inhibition was dependent on TLR-2 for MTB 19-kDa lipoprotein (but not whole MTB or the other PAMPs); inhibition was dependent on myeloid differentiation factor 88 for MTB and all of the individual PAMPs. Inhibition of MHC-II and alternate MHC-I processing was delayed, appearing after 16 h of PAMP exposure, as would occur in chronically infected macrophages. Despite inhibition of alternate MHC-I Ag processing, there was no inhibition of MHC-I expression, MHC-I-restricted presentation of exogenous peptide or conventional MHC-I processing of cytosolic Ag. MTB 19-kDa lipoprotein and other PAMPs inhibited phagosome maturation and phagosome Ag degradation in a myeloid differentiation factor 88-dependent manner; this may limit availability of peptides to bind MHC-I. By inhibiting both MHC-II and alternate MHC-I Ag processing, pathogens that establish prolonged infection of macrophages (>16 h), e.g., MTB, may immunologically silence macrophages and evade surveillance by both CD4(+) and CD8(+) T cells, promoting chronic infection.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Aaron A R
authors.initials: AA
authors.lastname: Tobian
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Potter
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Ramachandra
authors.forename: Rish K
authors.initials: RK
authors.lastname: Pai
authors.forename: Marilyn
authors.initials: M
authors.lastname: Convery
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000943:Antigens, Differentiation / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D002458:Cell Fractionation; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology*; D008074:Lipoproteins / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
chemical_list: C087864:19 kDa antigen, Mycobacterium; D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors