title: CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells.
abstract: Integrin-associated protein (CD47) is a broadly expressed protein that costimulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating alloresponses, CD47(+/+) or CD47(-/-) T cells were infused into irradiated or nonconditioned major histocompatibility complex disparate recipients. Graft-versus-host disease lethality was markedly reduced with CD47(-/-) T cells. Donor CD47(-/-) 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 that CD47(-/-) T cells and marrow cells were cleared by the innate immune system. To address this hypothesis, dye-labeled CD47(-/-) and CD47(+/+) lymphocytes or marrow cells were infused in vivo and clearance was followed. Dye-labeled CD47(-/-) cells were engulfed by splenic dendritic cells and macrophages resulting in the clearance of virtually all CD47(-/-) lymphohematopoietic cells within 1 day after infusion. Host phagocyte-depleted CD47(+/+) recipients partially accepted allogeneic CD47(-/-) T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulated CD47 density. CD47 expression may be a critical indicator for determining whether lymphohematopoietic cells will survive or be cleared.
authors.affiliation: University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. blaza001@tc.umn.edu
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: F P
authors.initials: FP
authors.lastname: Lindberg
authors.forename: E
authors.initials: E
authors.lastname: Ingulli
authors.forename: A
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: P A
authors.initials: PA
authors.lastname: Oldenborg
authors.forename: K
authors.initials: K
authors.lastname: Iizuka
authors.forename: W M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000276:immunology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000378:metabolism*; D015536:Down-Regulation; D006086:Graft vs Host Disease; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D023421:Models, Animal; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D011971:Receptors, Immunologic