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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.