Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells

Macrophages recognize CD47 as a marker of "self" and phagocytose CD47(null) hematopoietic cells. Using CD47 chimera models, here, we show that the phagocytic activity of macrophages against CD47(null) hematopoietic cells is conferred by CD47 expression on nonhematopoietic cells, and this "education" process is hematopoietic cell-independent. Macrophages in the chimeras where nonhematopoietic cells express CD47 phagocytose CD47(null) cells, whereas those in the chimeras lacking CD47 on nonhematopoietic cells are tolerant to CD47(null) cells. However, macrophages in the latter chimeras retain phagocytic activity against CD47(null) RBCs, demonstrating a split macrophage tolerance to CD47(null) hematopoietic cells. The findings highlight the potential importance of nonhematopoietic cells in the regulation of macrophage function, and suggest a previously uncharacterized mechanism of macrophage tolerance.