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PubMed1999

A sensitive immunoassay for rat fatty acid translocase (CD36) using phage antibodies selected on cell transfectants: abundant presence of fatty acid translocase/CD36 in cardiac and red skeletal muscle and up-regulation in diabetes.

The rat membrane protein fatty acid translocase (FAT), which shows sequence similarity to human CD36 (a membrane protein supposedly involved in a variety of membrane processes), is implicated in the transport of long-chain fatty acids across cellular membranes. To set up an immunoassay for quantification of FAT in different tissues, we isolated a series of anti-FAT antibodies by panning a large naive phage antibody library on FAT-transfected H9c2 cells. All seven different phage antibody fragments isolated reacted specifically with FAT, and most likely recognize the same or closely located immunodominant sites on FAT, as a competitive monoclonal antibody (mAb) (CLB-IV7) completely blocked the binding of all these phage antibodies to cells. A sandwich ELISA was set up using mAb 131. 4 (directed against purified CD36 from human platelets) as capture antibody and phage antibodies and anti-phage sera as detector. With this ELISA (sensitivity 0.05 microgram/ml), the FAT content in isolated cardiomyocytes was found to be comparable with that of total heart ( approximately 3 mg/g of protein), while liver tissue and endothelial cells were below the detection limit (<0.1 mg of FAT/g of protein). During rat heart development, protein levels of FAT rose from 1.7+/-0.7 mg/g of protein on the day before birth to 3.6+/-0.4 mg/g of protein on day 70. Comparing control with streptozotocin-induced diabetic rats, a statistically significant (P<0.05) 2-4-fold increase of FAT was seen in heart (from 4.2+/-2.3 to 11.0+/-5.7 mg/g of protein), soleus (from 0.6+/-0.1 to 1.4+/-0.5 mg/g of protein) and extensor digitorum longus (EDL) muscle (from 0.3+/-0.1 to 1. 2+/-0.8 mg/g of protein). In addition, the FAT contents of each of these muscles were found to be of similar magnitude to the contents of cytoplasmic heart-type fatty-acid-binding protein in both diabetic rats and controls, supporting the suggested roles of these two proteins in cellular fatty acid metabolism. This is the first time phage display technology has been succesfully applied for direct selection, from a large naive antibody library, of antibodies that recognize selected membrane proteins in their natural context.

Animals↗
PubMed2005

Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10.

OBJECTIVE: Marked anti-atheromatous effects of the anti-inflammatory cytokine interleukin-10 (IL-10) were observed in several lipid-driven animal models of arteriosclerosis. We therefore investigated whether IL-10 affects macrophage cholesterol handling. METHODS: Human THP-1 cells and peripheral monocytes served as macrophage models. Specific mRNA was quantified by real-time RT-PCR, protein expression by flow cytometry and Western blotting. Cellular cholesterol handling was studied by lipoprotein-facilitated uptake and efflux assays. IL-10 effects were also studied in cells transfected with liver X receptor alpha (LXRalpha)-siRNA or a LXRalpha response element (LXRE) reporter construct. RESULTS: Picomolar IL-10 suppressed basal and peroxisome proliferator-activated receptor gamma (PPARgamma)-stimulated transcription of the scavenger receptor CD36 due to reduced PPARgamma protein expression. In contrast, IL-10 stimulated transcription of the active cellular cholesterol exporters ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1) and the LDL receptor, whereas scavenger receptor-BI (SR-BI) was unchanged. The reduction of CD36 and stimulation of ABCA1 expression was confirmed in human monocytes. Thereby, IL-10 prevented cellular cholesterol overloading from oxidized LDL (oxLDL) and enhanced efflux to apoA-containing particles initiating reverse cholesterol transport. Experiments with inhibitors, LXRalpha silencing and the LXRE reporter gene construct supported the proximal transmission of the IL-10 effect on ABCA1 by the IL-10 receptor/signal transducer and activator of transcription 3 (STAT3) pathway and distal cross-talk to the LXRalpha and PPARalpha/retinoic acid X receptor (RXR) and cAMP/protein kinase A (PKA) pathways. CONCLUSIONS: In addition to immune and anti-inflammatory actions, IL-10 redirects macrophage cholesterol handling towards reverse cholesterol transport, which contributes to its anti-atherosclerotic action.

ATP Binding Cassette Transporter 1↗
PubMed1994

Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells.

Src-related cytoplasmic PTKs are physically and functionally associated with cell surface receptors and are involved in signal transduction. In this paper we report the identification of src-related proteins p59fyn, pp60c-src and p62yes in human microvascular endothelial cells cultured from normal human skin and their physical association with the thrombospondin receptor CD36. Such an association represents a potential signalling pathway by which thrombospondin may regulate angiogenesis.

Antigens, CD↗
PubMed2004

The pivotal role of scavenger receptor CD36 and phagocyte-derived oxidants in oxidized low density lipoprotein-induced adhesion to endothelial cells.

Adhesion of phagocytes to endothelial cells constitutes a crucial step in atherogenesis. Oxidized low density lipoproteins (LDL) are supposed to facilitate the adhesion process. We investigated the molecular mechanisms by which mildly and extensively hypochlorite-oxidized LDL force adhesion of murine macrophages and human neutrophils to human umbilical venous endothelial cells. After 1h of co-incubation of macrophages, endothelial cells, and lipoproteins adhesion significantly increased to 160+/-13% (S.E.M., n=5) in the presence of mildly oxidized lipoprotein, and 210+/-11% (S.E.M., n=5) in the presence of extensively oxidized lipoprotein. Similar results were obtained with neutrophils. CD36 antibody (FA6-152) significantly reduced adhesion to 102+/-7% (S.E.M., n=5) using mildly oxidized low density lipoprotein and to 179+/-16% (S.E.M., n=5) using extensively oxidized low density lipoprotein. Native high density lipoprotein and to a lesser extent methionine-oxidized high density lipoprotein significantly counteracted the effects of low density lipoprotein. Prior incubation of endothelial cells with modified lipoproteins followed by their removal and subsequent incubation with macrophages or neutrophils resulted in only minor changes of adhesion. This suggests that the direct contact of low density lipoprotein with phagocytes followed by activation of a respiratory burst with release of reactive oxygen species facilitates the adhesion process. Accordingly, the addition of antioxidants (superoxide dismutase and catalase) to the co-incubation medium was followed by a significant decrease in phagocyte adhesion. It is concluded that oxidized low density lipoprotein-induced respiratory burst activation of phagocytes with subsequent release of oxidants constitutes a crucial step in promoting the adhesion of phagocytes to endothelial cells.

Animals↗
PubMed2006

Identification of CD36 as a new surface marker of marginal zone B cells by transcriptomic analysis.

Follicular (FO) B cells and marginal zone (MZ) B cells belong to the mature B cell population in spleen of mice. To identify new surface markers of these mature B cell subsets, we compared gene expression profiles of FO and MZ B cells by DNA microarray using FACS-sorted mouse FO and MZ B cells. From 14,000 mouse genes, 27 membrane proteins were expressed mainly in MZ B cells while another 22 membrane proteins expressed largely in FO B cells. Using FACS analysis, we identified that CD36, CD68, and CD49e were expressed on MZ B cells but not on FO B cells. In addition, using semi-quantitative PCR, we found that the mRNA of CD131 were much more abundant in MZ B cells. These results revealed new phenotypic properties of MZ and FO B cells, and would facilitate further studies in the differentiation and functions of these mature B cells.

Animals↗
PubMed2006

PPARgamma activation induces CD36 expression and stimulates foam cell like changes in rVSMCs.

The purpose of the present study was to determine the role of peroxisome proliferator-activated receptor gamma (PPARgamma) activation in smooth muscle cell (SMC) derived form cell formation. Wild and mutant type PPARgamma were delivered by adenovirus then activated with troglitazone. The result of Oil Red O staining and FACS analysis showed that PPARgamma activation induced lipid accumulation in rVSMCs. Furthermore, PPARgamma activation reduced SMC marker genes such as alpha-actin while induced adipocyte differentiation marker genes and lipid metabolism-related genes as evidenced by RT-PCR and fluorescent immunocytochemistry. All these data demonstrate that PPARgamma activation can drive foam cell like change in rVSMCs. Our results strongly suggest that PPARgamma expression induces CD36 expression and adipocyte differentiation gene activation in the process of atherosclerosis and might be one of the crucial events in SMC derived foam cell formation.

ATP Binding Cassette Transporter 1↗
PubMed1999

CD36 LIMPII analogous-1, a human homolog of the rodent scavenger receptor B1, provides the cholesterol ester for steroidogenesis in adrenocortical cells.

CD36 and LIMPII analogous-1 (CLA-1), a human homolog of the rodent scavenger receptor B1 (SR-B1), binds high-density lipoprotein (HDL) and mediates the selective uptake of HDL cholesterol ester (CE) by cultured transfected cells. CLA-1 is strongly expressed in steroidogenic tissues, including the adrenal gland, suggesting that CLA-1 plays a role in providing substrates for steroidogenesis. To address this, we established an adrenocortical cell line that highly expresses CLA-1. These cells increased CE uptake from HDL to 140.5% of the level in mock-transfected cells. After incubation of the transfected cells with HDL, corticosterone secretion from CLA-1-transfected cells increased to about two times the level in mock-transfected cells. These results indicate the possibility that CLA-1 (a close structural homolog of SR-B1)-mediated uptake of HDL CE may be a significant source of precursor cholesterol for steroidogenesis in humans as it is in mice.

Adrenal Cortex↗
PubMed2004

Octanoate stimulates cytosolic triacylglycerol accumulation and CD36 mRNA expression but inhibits acetyl coenzyme A carboxylase activity in primary cultured bovine mammary epithelial cells.

Mammary epithelial cells, which express and secrete leptin into milk, accumulate triacylglycerol (TAG). We examined effects on the accumulation of cytosolic TAG of addition of short- (acetate and butyrate) or medium- (octanoate) chain fatty acids to the medium bathing bovine mammary epithelial cells (bMEC). Octanoate stimulated the accumulation of TAG in a concentration-dependent manner from 1 to 10 mM and increased lipid droplet formation and mRNA expression of CD36 (a fatty acid translocase). Additionally, expression of a peroxisome proliferator activated receptor (PPAR) gamma 2 protein that is a lipid-activated transcription factor, was increased by the addition of acetate or octanoate. However, leptin mRNA expression was significantly reduced by addition of acetate or butyrate. Both short- and medium-chain fatty acids inhibited acetyl coenzyme A carboxylase (ACC) activities, which is pivotal in lipid synthesis, but elevated expression of uncoupling protein 2 (UCP2) mRNA, which is important in energy expenditure. These results suggest that octanoate induces cytosolic TAG accumulation and the formation of lipid droplets, and that acetate and butyrate inhibit leptin expression and lipid synthesis in bMEC.

Acetyl-CoA Carboxylase↗
PubMed2001

Interaction of S100A8/S100A9-arachidonic acid complexes with the scavenger receptor CD36 may facilitate fatty acid uptake by endothelial cells.

Recently, we showed that S100A8/A9 were secreted from phorbol ester-stimulated neutrophil-like HL-60 cells, thereby carrying arachidonic acid [Kerkhoff et al. (1999) J. Biol. Chem. 274, 32672-32679]. The present study was undertaken to evaluate whether the secreted S100A8/A9-AA complex might be involved in transcellular eicosanoid metabolism. In the presence of S100A8/A9, arachidonic acid was rapidly taken up by human umbilical vein endothelial cells in a saturable and energy-dependent fashion. Protein-facilitated arachidonate uptake was confirmed by its sensitivity toward the protein modifiers bromobimane and phloretin. Both potassium and sodium depletion did not affect the arachidonate transport, indicating that arachidonate influx was independent of endocytosis. The uptake of exogenous arachidonic acid by HUVEC was predominantly mediated by FAT/CD36. This conclusion was drawn by the findings that (i) arachidonate uptake was drastically inhibited by sulfo-N-succinimidyl oleate, a specific inhibitor of FAT/CD36; (ii) the maximal inhibition of arachidonate uptake induced by SSO was similar to that effected by ATP depletion; and (iii) the arachidonate transport was 2-fold higher in COS-7 cells transfected with the pEF.BOS-CD36 expression vector than in the empty vector-transfected COS-7 cells. Kinetic studies of arachidonate uptake were indicative for an interaction between fatty acid transporter and S100A8/A9-AA complex that was confirmed by an in vitro protein-protein interaction assay. FAT/CD36 has been suggested to be involved in inflammatory responses, and S100A8/A9 are released from activated leukocytes at inflammatory loci. Therefore, it can be envisioned that their interaction might propagate host response by perpetuating recruitment and activation of cellular effectors.

Animals↗
PubMed2003

Widespread functional specialization of Plasmodium falciparum erythrocyte membrane protein 1 family members to bind CD36 analysed across a parasite genome.

Plasmodium falciparum-infected erythrocytes sequester from blood circulation by binding host endothelium. A large family of variant proteins mediates cytoadherence and their binding specificity determines parasite sequestration patterns and potential for disease. The aim of the present study was to understand how binding properties are encoded into family members and to develop sequence algorithms for predicting binding. To accomplish these goals computational approaches and a binding assay were used to characterize adhesion across Plasmodium falciparum erythrocyte membrane 1 (PfEMP1) proteins in the 3D7 parasite genome. We report that most family members encode the capacity to bind CD36 in the protein's semi-conserved head structure and describe the sequence characteristics of a group of PfEMP1 proteins that do not. Structural and functional grouping of PfEMP1 proteins based upon head structure and additional domain architectural properties provide new insights into the protein family. These can be used to investigate the role of proteins in malaria pathogenesis and potentially tailor vaccines to recognize particular binding variants.

Algorithms↗
PubMed2000

clag9: A cytoadherence gene in Plasmodium falciparum essential for binding of parasitized erythrocytes to CD36.

The propensity of isolates of the malaria parasite Plasmodium falciparum to delete a segment of chromosome 9 has provided positional information that has allowed us to identify a gene necessary for cytoadherence. It has been termed the cytoadherence-linked asexual gene (clag9). clag9 encodes at least nine exons and is expressed in blood stages. The hydrophobicity profile of the predicted CLAG9 protein identifies up to four transmembrane domains. We show here that targeted gene disruption of clag9 ablated cytoadherence to C32 melanoma cells and purified CD36. DNA-induced antibodies to the clag9 gene product reacted with a polypeptide of 220 kDa in the parental malaria clone but not in clones with a disrupted clag9 gene.

Animals↗
PubMed1991

Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn, and Yes protein-tyrosine kinases in human platelets.

Activation of platelets with thrombin and other agonists causes a rapid increase in the phosphorylation of multiple proteins on tyrosine. To identify candidate protein-tyrosine kinases (PTKs; EC 2.7.1.112) that may be responsible for these phosphorylation events, we analyzed the expression of seven Src-family PTKs and examined the association of these kinases with known platelet membrane glycoproteins. Five Src-related PTKs were detected in platelets: pp60SRC, pp60FYN, pp62YES, pp61HCK, and two LYN products of Mr 54,000 and 58,000. The Fgr and Lck PTKs were not detected. Although strict comparative quantification of protein levels was not possible, pp60SRC was detected at higher levels than any of the other kinases. In addition, glycoprotein IV (GPIV, CD36), one of the major platelet membrane glycoproteins, was associated in a complex with the Fyn, Yes, and Lyn proteins in platelet lysates. Similar complexes were also found in two GPIV-expressing cell lines, C32 melanoma cells and HEL cells. Since PTKs appear to be involved in stimulus-response coupling at the plasma membrane, these results suggest that ligand interaction with GPIV may activate signaling pathways that are triggered by tyrosine phosphorylation.

Antigens, CD↗
PubMed1995

The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids.

The specific recognition of anionic phospholipids in the outer leaflets of cell membranes and lipoproteins by cell surface receptors may play an important role in a variety of physiologic and pathophysiologic processes (e.g. recognition of damaged or senescent cells by the reticuloendothelial system or lipoprotein homeostasis). Several investigators have described anionic phospholipid binding to cells, and phosphatidylserine (PS) binding to a partially purified approximately 95-kDa membrane protein has recently been reported (Sambrano, G.R., and Steinberg, D. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 1396-1400). Using both direct binding and ligand competition assays in transfected cells, we have found that two class B scavenger receptors, SR-BI and CD36, can tightly bind PS and phosphatidylinositol (PI)-containing liposomes (Kd for PS liposome binding to SR-BI is approximately 15 micrograms phospholipid/ml or 0.18 nM (mol PS liposomes/l), but not phosphatidylcholine, phosphatidylethanolamine, or sphingomyelin liposomes. PS and PI liposomes, but not the others, could effectively compete with PS liposomes and modified or native lipoproteins for binding to these receptors. Phosphatidic acid, another anionic phospholipid, could also compete, but was not as effective as PS or PI. Class B scavenger receptors are the first molecularly well-defined, specific cell surface receptors for anionic phospholipids to be described.

Animals↗
PubMed1999

Comparison of class B scavenger receptors, CD36 and scavenger receptor BI (SR-BI), shows that both receptors mediate high density lipoprotein-cholesteryl ester selective uptake but SR-BI exhibits a unique enhancement of cholesteryl ester uptake.

Scavenger receptor BI (SR-BI) mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without internalization and degradation of the HDL particle. The biochemical mechanism by which SR-BI mediates the selective uptake of HDL CE is poorly understood. Given that CE transfer will occur to some extent from HDL to protein-free synthetic membranes, one hypothesis is that the role of SR-BI is primarily to tether HDL close to the cell surface to facilitate CE transfer from the particle to the plasma membrane. In the present study, this hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Both mSR-BI and rCD36 bind HDL with high affinity, and both receptors mediate HDL CE selective uptake. However, SR-BI mediates selective uptake of HDL CE with a 7-fold greater efficiency than rCD36. HDL CE selective uptake mediated by rCD36 is dependent on HDL binding to the receptor, since a mutation that blocks HDL binding also blocks HDL CE selective uptake. These data lead us to hypothesize that one component of HDL CE selective uptake is the tethering of HDL particles to the cell surface. To explore the molecular domains responsible for the greater efficiency of selective uptake by mSR-BI, we compared binding and selective uptake among mSR-BI, scavenger receptor BII, and various chimeric receptors formed from mSR-BI and rCD36. The results show that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail also has a major influence on the selective uptake process.

Animals↗
PubMed2004

Changes in plasma membrane properties and phosphatidylcholine subspecies of insect Sf9 cells due to expression of scavenger receptor class B, type I, and CD36.

In mammalian cells scavenger receptor class B, type I (SR-BI), mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester into hepatic and steroidogenic cells. In addition, SR-BI has a variety of effects on plasma membrane properties including stimulation of the bidirectional flux of free cholesterol (FC) between cells and HDL and changes in the organization of plasma membrane FC as indicated by increased susceptibility to exogenous cholesterol oxidase. Recent studies in SR-BI-deficient mice and in SR-BI-expressing Sf9 insect cells showed that SR-BI has significant effects on plasma membrane ultrastructure. The present study was designed to test the range of SR-BI effects in Sf9 insect cells that typically have very low cholesterol content and a different phospholipid profile compared with mammalian cells. The results showed that, as in mammalian cells, SR-BI expression increased HDL cholesteryl ester selective uptake, cellular cholesterol mass, FC efflux to HDL, and the sensitivity of membrane FC to cholesterol oxidase. These activities were diminished or absent upon expression of the related scavenger receptor CD36. Thus, SR-BI has fundamental effects on cholesterol flux and membrane properties that occur in cells of evolutionarily divergent origins. Profiling of phospholipid species by electrospray ionization mass spectrometry showed that scavenger receptor expression led to the accumulation of phosphatidylcholine species with longer mono- or polyunsaturated acyl chains. These changes would be expected to decrease phosphatidylcholine/cholesterol interactions and thereby enhance cholesterol desorption from the membrane. Scavenger receptor-mediated changes in membrane phosphatidylcholine may contribute to the increased flux of cholesterol and other lipids elicited by these receptors.

Animals↗
PubMed2004

Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases.

Serum amyloid A protein (SAA) is an acute-phase reactant, known to mediate pro-inflammatory cellular responses. This study reports that CLA-1 (CD36 and LIMPII Analogous-1; human orthologue of the Scavenger Receptor Class B Type I (SR-BI)) mediates SAA uptake and downstream SAA signaling. Flow cytometry experiments revealed more than a 5-fold increase of Alexa-488 SAA uptake in HeLa cells stably transfected with CLA-1. Alexa 488-HDL uptake directly correlated with SAA uptake when determined in several CLA-1 stably transfected HeLa cell clones expressing various levels of CLA-1. SAA directly binds to CLA-1 as determined by cross-linking and colocalization of anti-CLA-1 antibody with SAA. SAA was co-internalized with transferrin to the endocytic recycling compartment pointing to a potential site of SAA metabolism. Alexa-488 SAA uptake in the CLA-1-overexpressing HeLa cells, as well as in THP-1 monocyte cell line, can be efficiently blocked by unlabeled SAA, high density lipoprotein, and other CLA-1 ligands. At the same time, markedly enhanced levels of phosphorylation of the mitogen-activated protein kinases (MAPKs), ERK1/2, and p38, were observed in cells stably transfected with CLA-1 cells following SAA stimulation when compared with mock transfected cells. The levels of the SAA-induced interleukin-8 (IL-8) secretion by CLA-1-overexpressing cells also significantly exceeded (5- to 10-fold) those detected for control cells. Synthetic amphipathic peptides possessing a structural alpha-helical motif inhibited SAA-induced activation of both MAPKs and IL-8 secretion in THP-1 cells. The results of this study demonstrate for the first time that CLA-1 functions as an endocytic SAA receptor and is involved in SAA-mediated cell signaling events associated with the immune-related and inflammatory effects of SAA.

Amino Acid Motifs↗
PubMed2005

Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycans.

Accumulating evidence indicates that secretory phospholipase A2 (sPLA2) enzymes promote atherogenic processes. We have previously showed the presence of Group V sPLA2 (GV sPLA2) in human and mouse atherosclerotic lesions, its hydrolysis of low density lipoprotein (LDL) particles, and the ability of GV sPLA2-modified LDL (GV-LDL) to induce macrophage foam cell formation in vitro. The goal of this study was to investigate the mechanisms involved in macrophage uptake of GV-LDL. Peritoneal macrophages from C57BL/6 mice (wild type (WT)), C57BL/6 mice deficient in LDL receptor (LDLR-/-), or SR-A and CD36 (DKO) were treated with control LDL, GV-LDL, oxidized LDL (ox-LDL) or LDL aggregated by vortexing (vx-LDL). As expected, ox-LDL induced significantly more cholesterol ester accumulation in WT and LDLR-/- compared with DKO macrophages. In contrast, there was no difference in the accumulation of GV-LDL or vx-LDL in the three cell types. 125I-ox-LDL exhibited high affinity, saturable binding to WT cells that was significantly reduced in DKO cells. Vx-LDL and GV-LDL showed low affinity, non-saturable binding that was similar for both cell types, and significantly higher compared with control LDL. GV-LDL degradation in WT and DKO cells was similar. Analyses by confocal microscopy indicated a distinct intracellular distribution of Alexa-568-labeled GV-LDL and Alexa-488-labeled ox-LDL. Uptake of GV-LDL (but not ox-LDL or vx-LDL) was significantly reduced in cells preincubated with heparin or NaClO3, suggesting a role for proteoglycans in GV-LDL uptake. Our data point to a physiological modification of LDL that has the potential to promote macrophage foam cell formation independent of scavenger receptors.

Animals↗
PubMed1998

Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes.

Dendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8(+) T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the alphavbeta5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the alphavbeta5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the alphavbeta5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

Antigen Presentation↗