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PMID: 17557120 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 117 ·No. 7 ·2007-07-00 ·Pages 1902-13

Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G

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-gamma 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.

MeSH Terms
Animals Antigen-Presenting Cells/cytology,metabolism Antigens, Surface/metabolism Apoptosis CD4-Positive T-Lymphocytes/cytology,immunology,metabolism Cancer Vaccines Cell Differentiation Gene Expression Regulation Granulocyte-Macrophage Colony-Stimulating Factor/deficiency,genetics,metabolism Homeostasis Immunotherapy Inflammation/genetics,metabolism,pathology Mice Mice, Inbred C57BL Mice, Knockout Milk Proteins/metabolism Neoplasms/immunology,metabolism,pathology,therapy Phagocytosis
Chemicals
Antigens, Surface Cancer Vaccines Mfge8 protein, mouse Milk Proteins Granulocyte-Macrophage Colony-Stimulating Factor
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jinushi Masahisa
Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Nakazaki Yukoh
Dougan Michael
Carrasco Daniel R
Mihm Martin
Dranoff Glenn
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI30966
Published
2007-07-00
Pages
1902-13
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1884688
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI30966 PMC Full Text View journal details
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