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Non-Canonical Functions of the Essential Autophagy Protein ATG5 in Antigen Processing and Presentation


Keller, Christian. Non-Canonical Functions of the Essential Autophagy Protein ATG5 in Antigen Processing and Presentation. 2017, University of Zurich, Faculty of Medicine.

Abstract

Autophagy comprises a group of cellular pathways that enables eukaryotic cells to deliver cytoplasmic constituents for lysosomal degradation, to recycle nutrients and to survive during starvation. In addition to these primordial functions, autophagy has emerged as a pivotal mechanism in orchestrating innate and adaptive immune responses. Autophagosomes intersect with MHC class II-containing compartments (MIICs) and autophagy-related proteins are known to support antigen loading for increased CD4+ T cell immunity. Reactivation and expansion of autoreactive CD4+ T cells within the central nervous system (CNS) are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). How encephalitogenic lymphocytes recognize the CNS as their target organ to induce inflammatory demyelination is incompletely understood. Our study shows that CNS dendritic cells (DCs) require expression of the autophagy protein ATG5 for myelin-specific CD4+ T cell reactivation. Mice with conditional deletion of ATG5 in CD11c+ DCs are completely resistant to develop adoptively tranferred EAE and depict substantially reduced CD4+ T cell expansion within the CNS. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. CD1d molecules survey endocytic compartments to bind lipid antigens in MIICs before recycling to the plasma membrane. We show that mice with DCspecific deletion of the essential autophagy gene Atg5 exhibited better CD1drestricted glycolipid presentation in vivo. These effects led to enhanced invariant Natural Killer T (iNKT) cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake and costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1d molecules via the adaptor protein complex 2 (AP2) and consequently increased surface expression of stimulatory CD1d-glycolipid complexes. Thus, ATG5 facilitates the recruitment of AP2 to CD1d molecules resulting in attenuated iNKT cell activation, which is in contrast to the supporting role of macroautophagy in CD4+ T cell stimulation. These results illustrate that the use and function of ATG5 is context-dependent therefore a clear and comprehensive concept of how the autophagy machinery couples to antigen-presentation and lymphocyte activation appears to be required to predict the outcome of therapeutic interventions in this pathway to boost adaptive immunity.

Abstract

Autophagy comprises a group of cellular pathways that enables eukaryotic cells to deliver cytoplasmic constituents for lysosomal degradation, to recycle nutrients and to survive during starvation. In addition to these primordial functions, autophagy has emerged as a pivotal mechanism in orchestrating innate and adaptive immune responses. Autophagosomes intersect with MHC class II-containing compartments (MIICs) and autophagy-related proteins are known to support antigen loading for increased CD4+ T cell immunity. Reactivation and expansion of autoreactive CD4+ T cells within the central nervous system (CNS) are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). How encephalitogenic lymphocytes recognize the CNS as their target organ to induce inflammatory demyelination is incompletely understood. Our study shows that CNS dendritic cells (DCs) require expression of the autophagy protein ATG5 for myelin-specific CD4+ T cell reactivation. Mice with conditional deletion of ATG5 in CD11c+ DCs are completely resistant to develop adoptively tranferred EAE and depict substantially reduced CD4+ T cell expansion within the CNS. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. CD1d molecules survey endocytic compartments to bind lipid antigens in MIICs before recycling to the plasma membrane. We show that mice with DCspecific deletion of the essential autophagy gene Atg5 exhibited better CD1drestricted glycolipid presentation in vivo. These effects led to enhanced invariant Natural Killer T (iNKT) cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake and costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1d molecules via the adaptor protein complex 2 (AP2) and consequently increased surface expression of stimulatory CD1d-glycolipid complexes. Thus, ATG5 facilitates the recruitment of AP2 to CD1d molecules resulting in attenuated iNKT cell activation, which is in contrast to the supporting role of macroautophagy in CD4+ T cell stimulation. These results illustrate that the use and function of ATG5 is context-dependent therefore a clear and comprehensive concept of how the autophagy machinery couples to antigen-presentation and lymphocyte activation appears to be required to predict the outcome of therapeutic interventions in this pathway to boost adaptive immunity.

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Additional indexing

Item Type:Dissertation
Referees:Lünemann Jan, Münz Christian, Becher Burkhard
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:7 May 2017
Deposited On:20 Feb 2018 15:02
Last Modified:20 Mar 2018 00:43
OA Status:Green
Related URLs:http://www.recherche-portal.ch/ZAD:default_scope:ebi01_prod011030050 (Library Catalogue)

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