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- Title
MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF.
- Authors
Jinushi, Masahisa; Nakazaki, Yukoh; Dougan, Michael; Carrasco, Daniel R.; Mihm, Martin; Dranoff, Glenn
- 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.
- Subjects
GRANULOCYTE-macrophage colony-stimulating factor; COLONY-stimulating factors (Physiology); APOPTOSIS; AUTOIMMUNITY; GENETIC mutation
- Publication
Journal of Clinical Investigation, 2007, Vol 117, p1902
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI30966