Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens.
Injection of apoptotic cells can induce suppression of immune responses to cell-associated antigens. Here, we show that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) reduced MOG-specific T cell response and prevented the development of EAE. Since injected apoptotic cells accumulated initially in the splenic marginal zone (MZ), the role of macrophages in the MZ in immune suppression was examined using transgenic mice in which these cells could be transiently deleted by diphtheria toxin (DT) injection. DT-treated mice became susceptible to EAE even though MOG-expressing apoptotic cells were preinjected. Deletion of the macrophages caused delayed clearance of injected dying cells in the MZ. In wild-type mice, injected apoptotic cells were selectively engulfed by CD8 alpha(+) DCs, which are responsible for suppression of immune responses to cell-associated antigens. In contrast, deletion of macrophages in the MZ caused aberrant phagocytosis of injected dying cells by CD8 alpha(-)CD11b(+) DCs. These results indicate that macrophages in the MZ regulate not only efficient clearance of apoptotic cells but also selective engulfment of dying cells by CD8 alpha(+) DCs and that functional failure of these unique macrophages impairs suppression of immune responses to cell-associated antigens.
Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Yasunobu
Y
Miyake
Kenichi
K
Asano
Hitomi
H
Kaise
Miho
M
Uemura
Manabu
M
Nakayama
Masato
M
Tanaka
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004167:Diphtheria Toxin / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D001324:Autoantigens; D039481:CD11b Antigen; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D004167:Diphtheria Toxin; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein