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Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell–associated antigens
Yasunobu Miyake, … , Manabu Nakayama, Masato Tanaka
Yasunobu Miyake, … , Manabu Nakayama, Masato Tanaka
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2268-2278. https://doi.org/10.1172/JCI31990.
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Research Article Immunology

Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell–associated antigens

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Abstract

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 CD8α+ 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 CD8α–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 CD8α+ DCs and that functional failure of these unique macrophages impairs suppression of immune responses to cell-associated antigens.

Authors

Yasunobu Miyake, Kenichi Asano, Hitomi Kaise, Miho Uemura, Manabu Nakayama, Masato Tanaka

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Figure 1

Expression of HB-EGF–MOG fusion proteins in W3/MOG cells.

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Expression of HB-EGF–MOG fusion proteins in W3/MOG cells.
(A) Schematic ...
(A) Schematic diagrams of the HB-EGF–MOG fusion protein constructs. The amino acids 32–97 (HB-EGF–MOG-S) or 1–120 (HB-EGF–MOG-L) of MOG are attached at the C terminus of the signal (SIG), extracellular (EC), and transmembrane (TM) domains of HB-EGF. (B) Expression of HB-EGF–MOG/FLAG on the cell surface of transformants. W3 cells and their transformants expressing HB-EGF–MOG-S (W3/MOG-S) or HB-EGF–MOG-L (W3/MOG-L) were stained with Alexa Fluor 488–conjugated anti–HB-EGF antibody and analyzed by flow cytometry. (C) Immunodetection of HB-EGF–MOG proteins in the transformants. W3 cells (lanes 1, 4, and 7) and W3 cells expressing MOG-S (lanes 2, 5, and 8) or MOG-L (lanes 3, 6, and 9) were lysed and analyzed by Western blotting (WB) with anti–HB-EGF antibody (lanes 1–3). In order to confirm the expression of full-length HB-EGF–MOG/FLAG fusion proteins, cell lysates were subjected to immunoprecipitation with an anti-FLAG antibody. Immunoprecipitates were analyzed by Western blotting with anti–HB-EGF (lanes 4–6) or anti-MOG antibodies (lanes 7–9). (D) Induction of apoptosis in W3 cells and their transformants. W3 cells and their transformants were treated with (solid line) or without (dashed line) recombinant Fas ligand for 4 hours. Cells were then stained with PE-conjugated annexin V and analyzed by flow cytometry. More than 95% of W3 and W3/MOG cells underwent apoptosis by treatment with Fas ligand.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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