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

J Clin Invest. 2007 Jul;117(7):1902-13. doi: 10.1172/JCI30966.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / cytology*
  • Antigen-Presenting Cells / metabolism*
  • Antigens, Surface / metabolism*
  • Apoptosis*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines
  • Cell Differentiation
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / deficiency
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Homeostasis
  • Immunotherapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Milk Proteins / metabolism*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Phagocytosis


  • Antigens, Surface
  • Cancer Vaccines
  • Mfge8 protein, mouse
  • Milk Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor