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* Department of Immunology and
Division of Infectious Diseases, Veterans Affairs Medical Center and University of California, San Francisco, and
Department of Microbiology and Immunology, University of California, San Francisco, CA 94121
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chimeric receptor by both bacteria and dextran sulfate. Finally, we demonstrate binding of TREM-2A/Ig fusion to a series of human astrocytoma lines but not to a variety of other cell lines. The binding to astrocytomas, like binding to bacteria, is inhibited by anionic bacterial products, suggesting either a similar charge-based ligand recognition method or overlapping binding sites for recognition of self- and pathogen-expressed ligands. |
Introduction |
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Recent studies by Colonna and colleagues (4) demonstrate that TREM-1 plays a critical role in the inflammatory response to infection. They found that the expression of TREM-1 is increased on myeloid cells in response to both bacterial and fungal infections in humans. Similarly, in mice the induction of shock by LPS is associated with increased expression of TREM-1. Furthermore, treatment of mice with a soluble TREM-1/Ig fusion protein, as a "decoy" receptor, protects mice from death due to LPS. Thus, TREM-1 is up-regulated by infection and its blockade reduces death in a model for septic shock.
In contrast to TREM-1, human TREM-2 is not constitutively expressed on neutrophils or on monocyte/macrophages. Its expression can be induced, however, on human dendritic cells grown from blood monocytes by culture in GM-CSF and IL-4 (5). Stimulation of TREM-2 on these cells up-regulates CCR7, a chemokine receptor for CCL19 (EBI-1 ligand chemokine, macrophage-inflammatory protein 3
) and CCL21 (secondary lymphoid tissue chemokine) that is important in the migration of dendritic cells to lymph nodes (7). Humans deficient in TREM-2 develop degenerative brain disease and bone cysts (8), a clinical presentation that is similar if not identical to humans lacking DAP12 (9). Less dramatic changes in brain and bone have also been described in DAP12-deficient mice (10), which also accumulate dendritic (Langerhans) cells in the skin (11), and are resistant to experimental autoimmune encephalitis (12). Thus, TREM-2 is important in maintenance of the normal architecture of bone and brain.
No ligands for any of the TREM receptors have been identified. In this study, we demonstrate that mouse TREM-2A and TREM-2B, but not TREM-3, bind to both Gram-positive and Gram-negative bacteria as well as to astrocytoma cell lines. Binding by TREM-2 is inhibited by purified anionic bacterial products, suggesting that TREM-2 receptors may bind both bacteria and astrocytes via a charge-dependent interaction. Thus, pattern recognition of anionic ligands by TREM-2 receptors may extend both to pathogens and to self-Ags.
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Materials and Methods |
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The BWZ.36 (BWZ) mouse T cell lymphoma cell line (13) was kindly provided by N. Shastri (University of California, Berkeley, CA). This line does not express endogenous TREM receptors. The astrocytoma lines SF126, SF210, SF268, SF295 (14), U251, U343, U373 (15) and A172 (16) were obtained from the University of California, San Francisco(UCSF)/Neurosurgery Tissue Bank. All other cell lines came from the American Type Culture Collection (Manassas, VA). All cell lines were grown in RPMI 1640 supplemented with 5% heat-inactivated FBS, 25 µM 2-ME, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin (cRPMI). The M2 anti-FLAG mAb, dextran sulfate, polyinosinic acid, heparin, chondroitin sulfate, and lipoteichoic acid (LTA) were purchased from Sigma-Aldrich (St. Louis, MO). Peptidoglycan was purchased from Fluka (St. Louis, MO). LPS was purchased from List Biological Laboratories (Campbell, CA).
Bacteria and fungi
BODIPY-conjugated Escherichia coli and Staphylococcus aureus (Bioparticles) were purchased from Molecular Probes (Eugene, OR). The S. aureus Wood strain lacks protein A expression and thus does not bind Ig. E. coli TG1 strain was grown in Luria-Bertani broth. Enterococcus faecalis INY3000, Streptococcus pyogenes ATCC 19615, and Staphylococcus xylosus ATCC 29971 were grown in Todd-Hewitt broth. Pseudomonas aeruginosa ATCC 10145 and Proteus mirabilis ATCC 7002 were grown in brain-heart infusion broth or thioglycolate broth. Candida albicans ATCC 14053 and Candida guilliermondii ATCC 6260 were grown in Sabouraud’s dextrose broth.
Production of fusion proteins
Fc fusion proteins were constructed in a pCDM8 vector containing a SLAM leader sequence (aa 1–24 of SLAM (NP_038758.1) and human IgG1 Fc domain (aa 243–473 of IgG1 (CAA75030); kindly provided by L. Lanier, UCSF). A XhoI site 3' to the leader and a further XhoI site 5' of the IgG1 Fc domain allowed cloning of cDNA encoding aa 19–171 of TREM-2 (AAK01465) or aa 20–135 of TREM-3 (NP_067382). The chimeric cDNAs were shuttled into the pcDNA4 vector (Stratagene, La Jolla, CA). Integrity of the constructs was confirmed by sequencing. 293T cells in exponential growth were transfected with 3 µg of plasmid DNA using FuGENE (Roche, Indianapolis, IN), and transfected cells were selected in cRPMI containing 0.75 mg/ml Zeocin (Invitrogen, Carlsbad, CA). Ig fusion protein was purified from conditioned medium using protein G affinity chromatography.
Expression of TREM-2 or TREM-3 on BWZ cells
For expression of TREM-2 or TREM-3 on BWZ cells, we constructed a vector containing a CD8 leader sequence (aa 1–21, AAH25715) and FLAG tag (using a vector kindly provided by L. Lanier, UCSF), and downstream of this, a CD8 transmembrane domain (aa 187–215, AAH25715) and the CD3 cytoplasmic domain (aa 216–327, AAF34793) (using a vector kindly provided by A. Weiss, UCSF). A ClaI site 3' to the FLAG tag and a BamHI site 5' of the CD8 transmembrane domain allowed cloning of cDNA encoding aa 19–171 of TREM-2 (AAK01465) and aa 20–135 of TREM-3 (NP_067382). The chimeric cDNA was shuttled into the pcDNA4 vector (Stratagene) and integrity of the constructs was confirmed by sequencing. BWZ cells were transfected by electroporation and selected in cRPMI containing 0.75 mg/ml Zeocin (Invitrogen).
BWZ reporter assay
The BWZ line was derived from BW5147 T cells and contains a lacZ reporter construct regulated by four copies of the NFAT promoter element (13). BWZ cells or TREM-transfected BWZ cells were seeded in 96-well plates at 1 x 105 cells/well in cRPMI supplemented with 10 ng/ml PMA. Bacteria (heat-killed E. coli) or carbohydrate ligands were added at the concentrations detailed in the figures. Plates were incubated for 16 h at 37°C in a 5% CO2 humidified atmosphere. Cells were washed once in PBS and lacZ activity was determined by incubating the cells with 150 µM chlorophenol red--D-galactopyranoside in PBS supplemented with 100 mM 2-ME, 9 mM MgCl2, and 0.125% Nonidet P-40. After sufficient color development, absorbance was measured at 595 nm and corrected for background absorbance at 650 nm. Values were normalized by subtracting the absorbance of wells treated with PMA alone.
Flow cytometric analysis and confocal microscopy
All binding steps were conducted at 4°C in PBS/0.02% azide. Bacteria were stained with TREM/Ig fusion protein at 10 µg/ml. For blocking studies, the concentrations of blocking agents are noted in Results. The blocking agents were first mixed with TREM-2A/Ig fusion protein and incubated for 5 min before adding to bacteria. Relative TREM-2A-Fc binding was derived by dividing mean fluorescence intensity in the presence of each inhibitor concentration by mean fluorescence intensity without inhibitor and multiplying by 100. For the bacterial binding studies, killed E. coli or S. aureus labeled with the fluor BODIPY (Molecular Probes) were used at 0.5 mg (cell weight)/ml in PBS/0.02% azide. After removal of unbound bacteria by washing in PBS/0.02% azide followed by centrifugation at 75 x g for 3 min, cells were analyzed on a FACScan flow cytometer (BD Biosciences, San Jose, CA) or resuspended in mounting medium, placed on a slide, and analyzed by confocal microscopy.
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Results |
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Soluble TREM-2A/Ig bound at high levels both to Bioparticles S. aureus and to E. coli (Fig. 1). Binding was not seen with TREM-3/Ig or with human IgG1 (Fig. 1 and data not shown). These bacteria had been modified by conjugation to the BODIPY fluor, but this was not the cause of binding by TREM-2A, because TREM-2A/Ig bound also to fresh (unconjugated) E. coli as well as to a variety of other freshly prepared bacteria, both Gram-negative (P. mirabilis) and Gram-positive (S. pyogenes and E. faecalis; Fig. 1). In contrast, little binding was observed to P. aeruginosa (Gram-negative) or S. xylosus (Gram-positive; Fig. 1). Binding was also seen with some yeast (C. guermundii) but not all (e.g., C. albicans; Fig. 1). These studies show broad binding of microorganisms by TREM-2 but not TREM-3.
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To further exclude a role for the Ig portion of the chimeric protein and to assess whether TREM-2 binding of bacteria could occur on the surface of cells expressing TREM-2, we next examined the binding of bacteria to BWZ cells transfected with TREMs. BWZ cells transfected with chimeric TREM-2A or TREM-2B (variants of TREM-2 that differ by three amino acids) (3) or with TREM-3 were examined for their capacity to bind BODIPY-labeled S. aureus or E. coli. Expression levels of TREM-2A, TREM-2B, and TREM-3 on the BWZ cells were equivalent, as detected by FLAG expression (Fig. 2A). Cells expressing TREM-2A or TREM-2B bound S. aureus and E. coli, but untransfected cells or cells transfected with TREM-3 did not. Binding of bacteria to cells transfected with TREM-2 was confirmed by using confocal microscopy (Fig. 3). Occasional bacteria remained in washed TREM-3 transfectants, but in this instance the bacteria were rarely associated with the cells (Fig. 3).
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To confirm that the binding of bacteria to the cell surface of TREM-2 transfectants was dependent on TREM-2, we assessed binding of bacteria to the cell surface in the presence of TREM-2A/Ig or TREM-3/Ig fusion protein or control human IgG1. As shown in Fig. 2B, only TREM-2A/Ig fusion protein could block the binding of E. coli or S. aureus to the surface of TREM-2 transfectants; TREM-3/Ig or control IgG1 had no effect.
Binding of TREM-2A/Ig to bacteria can be blocked by anionic bacterial products and other anionic carbohydrates
To determine what structures TREM-2 might recognize on the surface of bacteria, we first attempted to block the binding of TREM-2A to bacteria using the bacterial products LPS (from E. coli), LTA (from S. aureus), or peptidoglycan (from S. aureus). To varying degrees, each of these bacterial products was able to reduce binding of TREM-2A/Ig to the surface of E. coli, but LTA, which is not expressed on E. coli or other Gram-negative organisms, gave the most complete inhibition at the lowest concentration (Fig. 4). Due to the nature of these reagents, molar concentration cannot be accurately calculated and it is possible that LTA is present at a higher molar ratio than the other reagents. Nevertheless, these results indicate that TREM-2A, but not TREM-3, can bind to LPS, peptidoglycan, or LTA. The finding that LTA is the most effective inhibitor also indicates that its capacity to block binding is not due to contamination by either of the other structures. These bacterial products all have repeated anionic residues. Scavenger receptors, which also bind to both Gram-positive and Gram-negative bacteria, do so through the use of pattern recognition of anionic ligands (17). We therefore examined whether or not charged carbohydrate polymers would also interfere with binding of TREM-2A/Ig to the surface of E. coli. Dextran sulfate (high molecular mass) strongly blocked binding of TREM-2A/Ig to E. coli (Fig. 4). Low molecular mass dextran sulfate also blocked binding, although less effectively. Polyinosinic acid, which blocks binding of anionic ligands by scavenger receptors, also inhibited TREM-2A/Ig binding to some degree, although less effectively than dextran sulfate. Heparin also gave only limited inhibition, while chondroitin sulfate did not significantly inhibit the binding of TREM-2A/Ig to E. coli even at high concentrations (Fig. 4). These findings support the hypothesis that TREM-2 receptors bind to bacteria through the recognition of anionic bacterial surface structures. The recognition of ligand, however, is not solely determined by charge and the pattern recognized by TREM-2 appears to differ from the pattern recognized by scavenger receptors.
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The BWZ cell lines that we used to assess the binding of bacteria by TREM-2A and TREM-2B utilized a construct in which these receptors are linked to the CD3 cytoplasmic domain. The BWZ cells contain a lacZ reporter gene under the control of NFAT, which can be activated by signaling through CD3. BWZ/TREM-2A cells induced lacZ expression when stimulated with low but not high concentrations of E. coli (Fig. 5). Furthermore, dextran sulfate at low but not high concentrations was also able to stimulate the BWZ/TREM-2A reporter line while chondroitin sulfate, which does not inhibit binding of bacteria to TREM-2, had no effect over the concentration range tested (Fig. 5). In contrast, none of these treatments was able to elicit a response from BWZ/TREM-3 or from untransfected BWZ (Fig. 5 and data not shown).
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The TREM-2A/Ig and TREM-3/Ig chimeric proteins were used to search for TREM ligands on host cells. Neither fusion protein showed significant binding to a variety of hemopoietic cell lines, including the B cell myeloma SP 2/0, the macrophage line P388D1, the mast cell line P815, or the T cell lymphoma EL4 (Fig. 6A). TREM-2A/Ig, however, brightly stained a series of astrocytoma lines of human origin, including SF126, SF210, SF268, and A172 (Fig. 6A). Similar staining was seen with SF295, U251, U343, and U373 astrocytoma lines, while no binding was seen to human hemopoietic lines, including Jurkat and RAMOS (data not shown). Binding of TREM-2 to astrocytoma cells, like binding to bacteria, was inhibited by the bacterial products LPS and LTA but not significantly by peptidoglycan (Fig. 6B). These results suggest that astrocytoma cells express a ligand for TREM-2 and that, as with recognition of bacteria, binding of the ligand is based at least in part on charge.
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Discussion |
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TREM-2 expression has been demonstrated on microglia (18) and the capacity of TREM-2 to bind to glial cells (astrocytomas) may relate to the clinical syndrome in humans with mutations in TREM-2, which includes brain degeneration as well as dysplasia of bones (8). This syndrome, called Nasu-Hakola disease, or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, is also seen in humans deficient in DAP12 (9). Thus, although many receptors utilize DAP12 as an adaptor molecule for cell signaling, at least some functions of TREM-2 are not redundant in function with other DAP12-associated receptors. TREM-2-deficient mice have not yet been described, but mice deficient in DAP12 have been studied, and they also show changes in brain and bone (10). Although TREM-2 binds to bacteria, neither humans nor mice deficient in TREM-2 are known to have increased susceptibility to bacterial infection. This has not been extensively studied, but it would be surprising if other mechanisms of host defense did not compensate, at least in part, for any role of TREM-2. Also, it should be noted that in Nasu-Hakola disease patients, some of the reported mutations in TREM-2 might still permit the expression of a secreted form of TREM-2. Likewise, DAP12-deficient humans and mice may express secreted TREM-2 (18, 19).
Using a sensitive reporter assay, we demonstrate transmembrane signaling via a TREM-2-CD3 chimeric receptor in response to both heat-killed bacteria and dextran sulfate. We have not, however, been able to detect a reproducible increase in TREM-2-associated DAP12 phosphorylation following stimulation of a dendritic cell line with bacteria (data not shown). This may reflect a lack of sensitivity of the detection reagents, or further signals may be necessary to give complete activation of DAP12 signaling in response to these ligands. Our studies suggest that TREM-2 can recognize multiple ligands without accessory proteins, but we cannot rule out that such complex formation is required for efficient signaling in response to these ligands. This may also explain why we see no signaling response to our astrocytoma lines (data not shown), despite a clear binding of TREM-2-Ig to these cells. The binding of a receptor to its ligand can of course lead to functional consequences in the absence of signaling. Thus, TREM-2 binding of its astrocyte ligand may allow adhesion of myeloid cells to astrocytes and thereby assist in localization of the myeloid cells or contribute to the stability of the cell-cell interaction. Also, TREM-2 may have activity as a soluble protein, independent of transmembrane signaling (18, 19).
The capacity of TREM-2 to bind broadly to both exogenous (bacterial) and endogenous (astrocytoma) ligands is a feature of many pattern recognition receptors, including the scavenger receptors, complement receptor 3, CD14, and several of the Toll-like receptors (reviewed in Ref.20). The scavenger receptors in particular bind both Gram-positive and Gram-negative bacteria through broad recognition of anionic ligands (17). Scavenger receptor recognition of these ligands is dependent, at least in part, on a series of positively charged residues in their cysteine-rich domains (21, 22). The structure of TREM-2 is unrelated to that of the scavenger receptors, but it includes a cluster of positively charged residues at the N terminus that might support binding of TREM-2 to charged carbohydrates. In support of this, Cantoni et al. (23) have recently resolved the crystal structure of NKp44, a receptor on NK cells with homology to TREM-2. The structure of NKp44 reveals a concentrated band of positive charge exposed on the surface of the molecule (42). It has previously been reported that NKp44 binds to viral hemagglutinin in a manner that is dependent on sialic acid (24). Thus, both TREM-2 and NKp44 may utilize charged residues in the recognition of ligands.
For bacteria, binding to soluble TREM-2 was confirmed by using a chimeric transmembrane TREM-2 receptor. The soluble transmembrane receptors share only the extracellular TREM-2 domain, indicating that binding is mediated by this domain. To exclude any contribution of TREM-2 that occurs only in chimeras, whether soluble or transmembrane, we have attempted to confirm binding of bacteria to cells transfected with native TREM-2 and FLAG-DAP12 (which is required for expression of TREM-2). However, our assay for bacterial binding requires high levels ofTREM-2 expression, probably because washing the cells generates high shear rates between the cells and bacteria. We could not attain sufficient expression of TREM-2, except in myeloid cells, which have other receptors for bacteria that obscure the assay. Nonetheless, even with relatively low levels of expression on 2B4 T cell hybridoma cells we could detect binding to bacterial products when they were expressed by phage; phage particles produced from E. coli bound specifically to TREM-2-expressing cells and binding was lost following extraction of LPS from the particles by using Triton X-114 (data not shown). Thus, native TREM-2 as well as chimeric TREM-2 specifically binds bacterial products.
The binding of TREM-2 to pathogens may be viewed in the light of other studies regarding other receptor families that contain both activating and inhibitory receptors. The members of the TREM family that have been studied (mouse TREM-1, TREM-2, and TREM-3; human TREM-1 and TREM-2) each associate with DAP12, a feature of activating receptors. In both the mouse and human genomes, however, there is at least one potential inhibitory member of this family, i.e., the structure predicts a cytoplasmic tail with an ITIM (2, 3). Other receptor families similarly have activating receptors that utilize DAP12 and inhibitory receptors that recruit the tyrosine phosphatases SHP-1 and SHP-2. These include the Ig-like receptor families human CD158 (killer Ig-like receptor) (25, 26) and the human signal regulatory proteins (27), as well as the lectin-like families, mouse Ly-49 (28); (29) and mouse or human CD94/NKG2 (30). All of the inhibitory members of these families recognize self-ligands: class I MHC for CD158 and Ly-49 receptors (25, 31, 32), nonclassical class I MHC Ags for CD94/NKG2A (HLA-E in humans (33), Qa-1b in mice (34)), and CD47 (integrin-associated protein) for signal regulatory protein 
1 (35). Activating CD94/NKG2C recognizes the same ligand as its inhibitory partner (36). There is also functional evidence that activating members of the killer Ig-like receptor and Ly-49 families recognize class I MHC Ags (37), but these interactions are less avid than binding by inhibitory receptors. Recent evidence suggests, however, that at least some of the activating receptors within these families recognize pathogen-associated ligands. Thus, Ly-49H recognizes a ligand expressed by mouse CMV, protein m157 (38). Additionally, two Ig-like activating proteins, NKp46 and NKp44, have been shown to bind to virally encoded hemagglutinins (24, 39). Of note, NKp44 is genetically linked to the TREM receptors, that were originally identified by their (limited) homology to NKp44. Neither NKp44 nor NKp46 are known to bind bacteria, although NKp46 has been shown to contribute to lysis of cells infected with Mycobacterium tuberculosis (40). Interestingly, both NKp44 and NKp46 have also been shown to contribute to the lysis of astrocytoma lines, including A172 (41). Thus, while inhibitory receptors that use ITIMs appear regularly to recognize self-ligands, it may be that related activating receptors can recognize pathogens as well as self, as is evidently the case for TREM-2.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael R. Daws, Department of Immunology 111R, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. E-mail address: mdaws{at}itsa.ucsf.edu
3 Abbreviations used in this paper: TREM, triggering receptor expressed by myeloid cells; DAP12, DNAX adaptor protein 12; TLT, TREM-like transcript; ITIM, immunoreceptor tyrosine-based inhibitory motif; SHP, Src homology protein; LTA, lipoteichoic acid.
Received for publication November 1, 2002. Accepted for publication May 8, 2003.
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