title: Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens.
abstract: Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8-/- mice spontaneously developed dermatitis associated with CD8+ T cell infiltration and striking activation of effector memory CD8+ T cells. CD8+ T cell responses to both exogenous and endogenous apoptotic cell-associated antigens were enhanced in Mfge8-/- mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8+ T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8-/- DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation.
authors.affiliation: Division of Rheumatology, University of Washington, Seattle, Washington 98195, USA. pengyf@u.washington.edu
authors.forename: YuFeng
authors.initials: Y
authors.lastname: Peng
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D003872:Dermatitis / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis; D021381:Protein Transport / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; C490919:Mfge8 protein, mouse; D008894:Milk Proteins