CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells

Integrin-associated protein (CD47) is a broadly expressed protein that cost imulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating allorespons es, CD47(+/+) or CD47(-/-) T cells were infused into irradiated or noncondi tioned major histocompatibility complex disparate recipients. Graft-versus- host disease lethality was markedly reduced with CD47(-/-) T cells. Donor C D47(-/-) T cells failed to engraft in immunodeficient allogeneic recipients . CD47(-/-) marrow was unable to reconstitute heavily irradiated allogeneic or congenic immune-deficient CD47(+/+) recipients. These data suggested th at CD47(-/-) T cells and marrow cells were cleared by the innate immune sys tem. To address this hypothesis, dye-labeled CD47(-/-) and CD47(+/+) lympho cytes or marrow cells were infused in vivo and clearance was followed. Dye- labeled CD47(-/-) cells were engulfed by splenic dendritic cells and macrop hages resulting in the clearance of virtually all CD47(-/-) lymphohematopoi etic cells within 1 day after infusion. Host phagocyte-depleted CD47(+/+) r ecipients partially accepted allogeneic CD47(-/-) T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulat ed CD47 density. CD47 expression may be a critical indicator for determinin g whether lymphohematopoietic cells will survive or be cleared.