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 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.
Blazar
B R
BR
University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. blaza001@tc.umn.edu
Lindberg
F P
FP
Ingulli
E
E
Panoskaltsis-Mortari
A
A
Oldenborg
P A
PA
Iizuka
K
K
Yokoyama
W M
WM
Taylor
P A
PA
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*
D015703:Antigens, CD; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D011971:Receptors, Immunologic