title: Alternative endogenous protein processing via an autophagy-dependent pathway compensates for Yersinia-mediated inhibition of endosomal major histocompatibility complex class II antigen presentation.
abstract: Extracellular Yersinia pseudotuberculosis employs a type III secretion system (T3SS) for translocating virulence factors (Yersinia outer proteins [Yops]) directly into the cytosol of eukaryotic cells. Recently, we used YopE as a carrier molecule for T3SS-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. We demonstrated that translocation of chimeric YopE/LLO into the cytosol of macrophages by Yersinia results in the induction of a codominant antigen-specific CD4 and CD8 T-cell response in orally immunized mice. In this study, we addressed the requirements for processing and major histocompatibility complex (MHC) class II presentation of chimeric YopE proteins translocated into the cytosol of macrophages by the Yersinia T3SS. Our data demonstrate the ability of Yersinia to counteract exogenous MHC class II antigen presentation of secreted hybrid YopE by the action of wild-type YopE and YopH. In the absence of exogenous MHC class II antigen presentation, an alternative pathway was identified for YopE fusion proteins originating in the cytosol. This endogenous antigen-processing pathway was sensitive to inhibitors of phagolysosomal acidification and macroautophagy, but it did not require the function either of the proteasome or of transporters associated with antigen processing. Thus, by an autophagy-dependent mechanism, macrophages are able to compensate for the YopE/YopH-mediated inhibition of the endosomal MHC class II antigen presentation pathway for exogenous antigens. This is the first report demonstrating that autophagy might enable the host to mount an MHC class II-restricted CD4 T-cell response against translocated bacterial virulence factors. We provide critical new insights into the interaction between the mammalian immune system and a human pathogen.
authors.affiliation: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany. holger.ruessmann@helios-kliniken.de
authors.forename: Holger
authors.initials: H
authors.lastname: Rüssmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Panthel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Köhn
authors.forename: Stefan
authors.initials: S
authors.lastname: Jellbauer
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Winter
authors.forename: Sara
authors.initials: S
authors.lastname: Garbom
authors.forename: Hans
authors.initials: H
authors.lastname: Wolf-Watz
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Silke
authors.initials: S
authors.lastname: Grauling-Halama
authors.forename: Gernot
authors.initials: G
authors.lastname: Geginat
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology* / Q000502:physiology; D001343:Autophagy / Q000276:immunology* / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology; D058947:Bacterial Secretion Systems / Q000276:immunology / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D011992:Endosomes / Q000276:immunology* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D015009:Yersinia Infections / Q000276:immunology; D015011:Yersinia pseudotuberculosis / Q000276:immunology* / Q000502:physiology; D015012:Yersinia pseudotuberculosis Infections / Q000276:immunology* / Q000503:physiopathology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D058947:Bacterial Secretion Systems; D000949:Histocompatibility Antigens Class II; C063239:yopE protein, Yersinia