CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors

Avice, Marie-Noëlle; Rubio, Manuel; Sergerie, Martin; Delespesse, Guy; Sarfati, Marika

doi:10.4049/jimmunol.165.8.4624

Cited by 77 publications

(63 citation statements)

References 62 publications

(49 reference statements)

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“…Ligation of CD47 by a soluble mAb reportedly inhibited IL-12 responsiveness by PHA-activated neonatal mononuclear cells (11). In the course of this study, we confirmed and extended these observations to activated adult PBMC.…”

Section: Cd47 Ligation Down-regulates Il-12 Responsivenesssupporting

confidence: 78%

“…When immobilized, CD47 mAb costimulated IL-2 production by CD3-activated normal or transformed adult T cells (17,18), whereas, in soluble form, it inhibited allogeneic MLR (19). It also decreased IL-2 production and IL-12R␤2 expression by IL-12-and PHAactivated naive cells; the latter is completely restored by addition of exogenous IL-2 at priming (11). Similarly, IL-2 abrogated the CD47 mAb-mediated inhibition of IL-12 responsiveness in anti-CD3-activated adult T cells (M. Sarfati, data not shown).…”

Section: Discussionmentioning

confidence: 88%

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Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-α: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation

Latour

Tanaka

Demeure

et al. 2001

The Journal of Immunology

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Proinflammatory molecules, including IFN-γ and IL-12, play a crucial role in the elimination of causative agents. To allow healing, potent anti-inflammatory processes are required to down-regulate the inflammatory response. In this study, we first show that CD47/integrin-associated protein, a ubiquitous multispan transmembrane protein highly expressed on T cells, interacts with signal-regulator protein (SIRP)-α, an immunoreceptor tyrosine-based inhibition motif-containing molecule selectively expressed on myelomonocytic cells, and next demonstrate that this pair of molecules negatively regulates human T and dendritic cell (DC) function. CD47 ligation by CD47 mAb or L-SIRP-α transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated CD4+ and CD8+ adult T cells without affecting their response to IL-2. Human CD47-Fc fusion protein binds SIRP-α expressed on immature DC and mature DC. SIRP-α engagement by CD47-Fc prevents the phenotypic and functional maturation of immature DC and still inhibits cytokine production by mature DC. Finally, in allogeneic MLR between mDC and naive T cells, CD47-Fc decreases IFN-γ production after priming and impairs the development of a Th1 response. Therefore, CD47 on T cells and its cognate receptor SIRP-α on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis by preventing the escalation of the inflammatory immune response.

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Section: Cd47 Ligation Down-regulates Il-12 Responsivenesssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 88%

Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-α: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation

Latour

Tanaka

Demeure

et al. 2001

The Journal of Immunology

Self Cite

217

189

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“…By contrast, the soluble SIRP␣1-Fc fusion protein, which efficiently bound CD47 (results not shown), had no apoptotic effect, regardless of the amount of protein or the incubation time we used. It is worth noting that only high concentrations of 4N1K (400 M) are able to induce cell death, whereas lower concentrations have been reported to sustain clonal expansion of inflammatory T cells (39) or to induce anergy of naive T cells (40,41). This apoptotic effect of 4N1K on T cells is not due to a nonspecific cytotoxicity, because CD47-deficient cells are resistant to cell death induced by 4N1K.…”

Section: Fig 2 Cd47 Interacts With the Bh3-only Protein Bnip3mentioning

confidence: 99%

CD47 and the 19 kDa Interacting Protein-3 (BNIP3) in T Cell Apoptosis

Lamy

Ticchioni

Rouquette-Jazdanian

et al. 2003

Journal of Biological Chemistry

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CD47 is a surface receptor that induces either coactivation or apoptosis in lymphocytes, depending on the ligand(s) bound. Interestingly, the apoptotic pathway is independent of caspase activation and cytochrome c release and is accompanied by early mitochondrial dysfunction with suppression of mitochondrial membrane potential (⌬⌿m). Using CD47 as bait in a yeast twohybrid system, we identified the Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3), a pro-apoptotic member of the Bcl-2 family, as a novel partner. Interaction between CD47 and the BH3-only protein was confirmed by immunoprecipitation analysis, and CD47-induced apoptosis was inhibited by attenuating BNIP3 expression with antisense oligonucleotides. Finally, we showed that the C-terminal domain of thrombospondin-1 (TSP-1), but not signal-regulatory protein (SIRP␣1), is the ligand for CD47 involved in inducing cell death. Immunofluorescence analysis of CD47 and BNIP3 revealed a partial colocalization of both molecules under basal conditions. After T cell stimulation via CD47, BNIP3 translocates to the mitochondria to induce apoptosis. These results show that the BH3-dependent apoptotic pathways, previously shown to be activated by intracellular pro-apoptotic events, can also be turned on by surface receptors. This new pathway results in a fast induction of cell death resembling necrosis, which is likely to play an important role in lymphocyte regulation at inflammatory sites and/or in the vicinity of thrombosis.

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“…CD47 may also function as a costimulator to regulate T cell activation, survival, and Th1 versus Th2 differentiation (4,5). Endogenous ligands for the extracellular domain of CD47 include the secreted protein thrombospondin-1 (TSP1) 1 and potentially other members of the thrombospondin family, several integrins (6 -9), and some members of the signal-regulatory protein family (3, 10 -13).…”

mentioning

confidence: 99%

Regulation of Integrin Function by CD47 Ligands

Barazi

Cashel

et al. 2002

Journal of Biological Chemistry

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CD47 (integrin-associated protein) is an integral membrane protein that is required for granulocyte and T cell recruitment to sites of infection (1, 2), and its absence on red blood cells leads to their rapid macrophage-mediated clearance (3). CD47 may also function as a costimulator to regulate T cell activation, survival, and Th1 versus Th2 differentiation (4, 5). Endogenous ligands for the extracellular domain of CD47 include the secreted protein thrombospondin-1 (TSP1) 1 and potentially other members of the thrombospondin family, several integrins (6 -9), and some members of the signal-regulatory protein family (3, 10 -13). Engagement of CD47 by soluble ligands or signal-regulatory protein counter receptors modulates several cell signaling pathways, including activation of a heterotrimeric G protein (14).Although some signal transduction through CD47 is integrin-independent (4, 15, 16), association of CD47 with certain integrins was found to modulate their function to mediate cell adhesion or motility (6,8,9,17). In addition to its known functional and physical interactions with ␣ v ␤ 3 , ␣ IIb ␤ 3 , and ␣ 2 ␤ 1 integrins, several publications have suggested an association of CD47 with ␣ 4 ␤ 1 integrin. CD47 and ␣ 4 ␤ 1 were colocalized on microvilli of K562 erythroleukemia cells (18), and CD47-dependent arrest of T cells on inflammatory endothelium could be blocked by antibodies that prevent ␣ 4 ␤ 1 integrin binding to VCAM-1 (2). In the latter study, ligation of CD47 by TSP1 or signal-regulatory protein 1␣ was inferred to activate ␣ 4 ␤ 1 integrin on T cells, although this was not demonstrated either functionally or biochemically.We recently found that CD47 expression is required for stimulation of T cell motility and expression of MMP-2 stimulated by ␣ 4 ␤ 1 integrin ligands (19). An antibody to CD47 also blocked the motility response to an ␣ 4 ␤ 1 integrin ligand (19). Therefore, at least a functional interaction occurs between CD47 and ␣ 4 ␤ 1 integrin.We identified a binding site for ␣ 4 ␤ 1 integrin in the Nterminal domains of TSP1 and TSP2 (19), whereas two binding sites for CD47 have been localized to the C-terminal domain of TSP1 (for review, see Ref. 20). Thus, TSP1 could potentially regulate its own interaction with ␣ 4 ␤ 1 integrin through simultaneous interactions with CD47 and ␣ 4 ␤ 1 integrin on a T cell, analogous to the ability of soluble TSP1 to stimulate ␣ v ␤ 3 integrin-dependent melanoma cell adhesion to immobilized TSP1 (21).To define a molecular basis for functional cross-talk between these two receptors, we have examined the effect of CD47 ligands on the function of ␣ 4 ␤ 1 integrin in T cells and melanoma cells. We confirmed that ligation of CD47 can activate ␣ 4 ␤ 1 integrin function but unexpectedly found the mechanism of this activity to be CD47 ligand-dependent. We further show that CD47 ligation differentially activates and inactivates ␣ v ␤ 3 and ␣ 4 ␤ 1 in melanoma cells and ␣ 4 ␤ 1 and ␣ 5 ␤ 1 in Jurkat cells. Unexpectedly, but consistent with a recent report demonstrating C...

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CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors

Cited by 77 publications

References 62 publications

Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-α: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation

Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-α: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation

CD47 and the 19 kDa Interacting Protein-3 (BNIP3) in T Cell Apoptosis

Regulation of Integrin Function by CD47 Ligands

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