title: Osteopontin in Spontaneous Germinal Centers Inhibits Apoptotic Cell Engulfment and Promotes Anti-Nuclear Antibody Production in Lupus-Prone Mice.
abstract: Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages. We indicate that osteopontin (OPN) secreted by CD153(+) senescence-associated T cells, which selectively accumulate in the GCs of lupus-prone mice, interferes with phagocytosis of apoptotic cells specifically captured via MFG-E8. OPN induced diffuse and prolonged Rac1 activation in phagocytes via integrin αvβ3 and inhibited the dissolution of phagocytic actin cup, causing defective apoptotic cell engulfment. In wild-type B6 mice, administration of TLR7 ligand also caused spontaneous GC reactions with increasing unengulfed apoptotic cells and ANA production, whereas B6 mice deficient for Spp1 encoding OPN showed less apoptotic cells and developed significantly reduced ANAs in response to TLR7 ligand. Our results suggest that OPN secreted by follicular CD153(+) senescence-associated T cells in GCs promotes a continuous supply of intracellular autoantigens via apoptotic cells, thus playing a key role in the progression of the autoreactive GC reaction and leading to pathogenic autoantibody production in lupus-prone mice.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Keiko
authors.identifier: 0000-0003-3886-3066
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Koyu
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and.
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Biochemistry and Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; minato@imm.med.kyoto-u.ac.jp hattori@ak.med.kyoto-u.ac.jp.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; minato@imm.med.kyoto-u.ac.jp hattori@ak.med.kyoto-u.ac.jp.
authors.forename: Masakazu
authors.identifier: 0000-0002-6160-2510
authors.initials: M
authors.lastname: Hattori
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D017209:Apoptosis; D053285:CD30 Ligand / Q000032:analysis; D002478:Cells, Cultured; D018858:Germinal Center / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000502:physiology; D053495:Osteopontin / Q000502:physiology*; D010587:Phagocytosis; D051199:Toll-Like Receptor 7 / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: D000974:Antibodies, Antinuclear; D053285:CD30 Ligand; D039302:Integrin alphaVbeta3; D008562:Membrane Glycoproteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C477038:Tlr7 protein, mouse; C505775:Tnfsf8 protein, mouse; D051199:Toll-Like Receptor 7; D053495:Osteopontin; D020830:rac1 GTP-Binding Protein