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. 2001 Aug 20;194(4):541-9.
doi: 10.1084/jem.194.4.541.

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

B R Blazar  1 , F P Lindberg, E Ingulli, A Panoskaltsis-Mortari, P A Oldenborg, K Iizuka, W M Yokoyama, P A Taylor
Affiliations

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

B R Blazar et al. J Exp Med. .

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.

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Figures

Figure 1
Figure 1
CD47−/− T cells have a reduced GVHD lethality capacity. (a) Nonirradiated, NK cell–depleted Balb/c SCID recipients (n = 5 per group) were given B6-CD47−/− or CD47+/+ T cells. Cell doses × 10−6 are indicated in parentheses. Recipients of 2 × 106 CD47−/− T cells had a significantly (P = 0.0015) higher survival rate versus those given 0.5 × 106 CD47+/+ T cells. (b) Irradiated (6.0 Gray TBI) bm1 recipients (n = 8 per group) were given B6-CD47−/− or B6-CD47+/+ CD8+ T cells. Recipients of CD47−/− T cells had a significantly higher survival versus B6-CD47+/+ T cells. (c) Irradiated (6.0 Gray TBI) bm12 recipients (n = 8 or 16 per group) were given B6-CD47+/+ CD4+ T cells. Recipients of B6-CD47−/− CD4+ T cells at a dose of 0.3 × 106 had a significantly higher survival rate than recipients of 10-fold fewer B6-CD47+/+ cells.
Figure 1
Figure 1
CD47−/− T cells have a reduced GVHD lethality capacity. (a) Nonirradiated, NK cell–depleted Balb/c SCID recipients (n = 5 per group) were given B6-CD47−/− or CD47+/+ T cells. Cell doses × 10−6 are indicated in parentheses. Recipients of 2 × 106 CD47−/− T cells had a significantly (P = 0.0015) higher survival rate versus those given 0.5 × 106 CD47+/+ T cells. (b) Irradiated (6.0 Gray TBI) bm1 recipients (n = 8 per group) were given B6-CD47−/− or B6-CD47+/+ CD8+ T cells. Recipients of CD47−/− T cells had a significantly higher survival versus B6-CD47+/+ T cells. (c) Irradiated (6.0 Gray TBI) bm12 recipients (n = 8 or 16 per group) were given B6-CD47+/+ CD4+ T cells. Recipients of B6-CD47−/− CD4+ T cells at a dose of 0.3 × 106 had a significantly higher survival rate than recipients of 10-fold fewer B6-CD47+/+ cells.
Figure 1
Figure 1
CD47−/− T cells have a reduced GVHD lethality capacity. (a) Nonirradiated, NK cell–depleted Balb/c SCID recipients (n = 5 per group) were given B6-CD47−/− or CD47+/+ T cells. Cell doses × 10−6 are indicated in parentheses. Recipients of 2 × 106 CD47−/− T cells had a significantly (P = 0.0015) higher survival rate versus those given 0.5 × 106 CD47+/+ T cells. (b) Irradiated (6.0 Gray TBI) bm1 recipients (n = 8 per group) were given B6-CD47−/− or B6-CD47+/+ CD8+ T cells. Recipients of CD47−/− T cells had a significantly higher survival versus B6-CD47+/+ T cells. (c) Irradiated (6.0 Gray TBI) bm12 recipients (n = 8 or 16 per group) were given B6-CD47+/+ CD4+ T cells. Recipients of B6-CD47−/− CD4+ T cells at a dose of 0.3 × 106 had a significantly higher survival rate than recipients of 10-fold fewer B6-CD47+/+ cells.
Figure 2
Figure 2
CD47+/+ but not CD47−/− BM rescues lethally irradiated recipients. (a) B6 recipients were given 6.5 Gray TBI and infused with Balb/c-CD47+/+ or CD47−/− BM (n = 15 per group). Recipients of CD47−/− BM had a significantly lower survival versus those given CD47+/+ BM. (b) Lethally irradiated (9.5 Gray TBI) B6-CD47−/− or B6-CD47+/+ Rag1−/− recipients (n = 15 per group) were infused with B6-CD47−/− BM. B6-CD47−/− recipients of B6-CD47−/− BM had a significantly higher survival than B6-CD47+/+Rag1−/− recipients given B6-CD47−/− BM.
Figure 2
Figure 2
CD47+/+ but not CD47−/− BM rescues lethally irradiated recipients. (a) B6 recipients were given 6.5 Gray TBI and infused with Balb/c-CD47+/+ or CD47−/− BM (n = 15 per group). Recipients of CD47−/− BM had a significantly lower survival versus those given CD47+/+ BM. (b) Lethally irradiated (9.5 Gray TBI) B6-CD47−/− or B6-CD47+/+ Rag1−/− recipients (n = 15 per group) were infused with B6-CD47−/− BM. B6-CD47−/− recipients of B6-CD47−/− BM had a significantly higher survival than B6-CD47+/+Rag1−/− recipients given B6-CD47−/− BM.
Figure 3
Figure 3
CD47−/− lymph node cells are cleared by APC in vivo. LN cells were isolated from B6-CD47+/+ or CD47−/− mice, CFSE-labeled, and injected (5 × 106 per mouse) intravenously into B6 recipients. Some mice were left uninjected (time 0 h). Spleens from mice were harvested 1, 2, and 4 h after injection (n = 3 per time point) and stained with mAb (anti-B220, anti-CD3, anti-CD11c, anti-CD11b, or anti-F4/80) to identify CD11b− DCs (B220−, CD3−, CD11c+), CD11b+ DCs (B220−, CD3−, CD11c+), and F4/80+ macrophages (B220−, CD3−, CD11c−). A portion of the spleens examined using confocal microscopic analysis. (a) Representative histograms depicting CD11b− DCs 1 h after injection of CD47+/+ cells (center), CD47−/− cells (bottom) or not injected (top) are shown. (b) Kinetics of the appearance of CFSE+CD11b−DCs (squares) CD11b+ DCs (circles), and F4/80+ macrophages (triangles) after injection of CD47+/+ (open symbols) or CD47−/− (closed symbols) LN cells. The percentage of CFSE+ cells contained within the indicated cell population is listed on the y axis. Values for standard error of the mean were all ≤26% except for CD11b+ DCs engulfing CD47+/+ T cells. At the indicated time points, there was a significantly (P ≥ 0.03) higher proportion of CD11b− CD11c+ (1, 2, 4 h) DCs, CD11b+ DCs (1 h), and F4/80+ macrophages (1 h) which had engulfed CFSE-labeled CD47−/− versus CD47+/+ cells. (c) Photomicrographs of spleen sections from mice at 1 h after injection with CFSE-labeled CD47+/+ (left) or CD47−/− (right) LN cells (green). CD11c+ DCs are red.
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