MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF
Masahisa Jinushi, Yukoh Nakazaki, Michael Dougan, Daniel R. Carrasco, Martin Mihm, Glenn Dranoff
Masahisa Jinushi, Yukoh Nakazaki, Michael Dougan, Daniel R. Carrasco, Martin Mihm, Glenn Dranoff
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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

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 7

MFG-E8 expression is downregulated upon antigen-presenting cell maturation.

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MFG-E8 expression is downregulated upon antigen-presenting cell maturati...
(A) Wild-type peritoneal macrophages were exposed to apoptotic cells and peptidoglycan (TLR2), poly-IC (TLR3), LPS (TLR4), or CpG (TLR9), and MFG-E8 expression was determined. Numbers refer to the percentage of cells within an indicated gate. (B) Engineered wild-type peritoneal macrophages were exposed to apoptotic cells with or without LPS, and supernatants were assayed by ELISA. (C) Transduced peritoneal macrophages were exposed to apoptotic cells with or without LPS and cocultured with allogeneic Balb/c splenocytes. Proliferation was determined by 3H-thymidine uptake. (D) Flt3-L– or GM-CSF–derived bone marrow dendritic cells were assayed for B220 and MFG-E8 expression. LPS or freeze-thaw–induced necrotic cells were added where indicated. (E) Flt3-L–derived dendritic cells were sorted into B220+ and B220– populations, exposed to apoptotic or necrotic cells, and assayed for cytokine production by ELISA. Similar results were obtained in at least 2 independent experiments. –, no TLR agonist added.