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MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF
Masahisa Jinushi, … , Martin Mihm, Glenn Dranoff
Masahisa Jinushi, … , Martin Mihm, Glenn Dranoff
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1902-1913. https://doi.org/10.1172/JCI30966.
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Research Article Oncology

MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF

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Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF–deficient mice develop inflammatory disease. Here we show that GM-CSF is required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8–mediated uptake of apoptotic cells is a key determinant of GM-CSF–triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF–deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-γ promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF–secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF–stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4+ T cell subsets in cancer and autoimmunity.

Authors

Masahisa Jinushi, Yukoh Nakazaki, Michael Dougan, Daniel R. Carrasco, Martin Mihm, Glenn Dranoff

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Figure 1

GM-CSF regulates the phagocytosis of apoptotic cells.

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GM-CSF regulates the phagocytosis of apoptotic cells.
(A) CFSE-labeled w...
(A) CFSE-labeled wild-type dying cells treated with dexamethasone (dex), etoposide, or necrotic cells were added to peritoneal macrophages, and phagocytosis was quantified by flow cytometry. Numbers refer to the percentage of cells within an indicated gate. (B) Purified splenic DCs or Flt3-L–derived bone marrow dendritic cells (BMDCs) were exposed to labeled apoptotic thymocytes, and phagocytosis was measured. (C) Peritoneal macrophages (3 mice per group) were loaded with apoptotic or necrotic thymocytes, and culture supernatants were measured by ELISA. (D) Peritoneal macrophages (circles, GM-CSF/IL-3/IFN-γ–deficient; squares, wild-type) were exposed to apoptotic (filled symbols) or necrotic (open symbols) thymocytes and cocultured with wild-type Balb/c splenocytes. Proliferation was determined by 3H-thymidine uptake. Results are representative of at least 2 or 3 independent experiments.

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