Pattern recognition by TREM-2: binding of anionic ligands.
We recently described the cloning of murine triggering receptor expressed by myeloid cells (TREM) 2, a single Ig domain DNAX adaptor protein 12-associated receptor expressed by cells of the myeloid lineage. In this study, we describe the identification of ligands for TREM-2 on both bacteria and mammalian cells. First, by using a TREM-2A/IgG1-Fc fusion protein, we demonstrate specific binding to a number of Gram-negative and Gram-positive bacteria and to yeast. Furthermore, we show that fluorescently labeled Escherichia coli and Staphylococcus aureus bind specifically to TREM-2-transfected cells. The binding of TREM-2A/Ig fusion protein to E. coli can be inhibited by the bacterial products LPS, lipoteichoic acid, and peptidoglycan. Additionally, binding can be inhibited by a number of other anionic carbohydrate molecules, including dextran sulfate, suggesting that ligand recognition is based partly on charge. Using a sensitive reporter assay, we demonstrate activation of a TREM-2A/CD3zeta 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.
Daws
Michael R
MR
Department of Immunology and Division of Infectious Diseases, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA. mdaws@itsa.ucsf.edu
Sullam
Paul M
PM
Niemi
Eréne C
EC
Chen
Thomas T
TT
Tchao
Nadia K
NK
Seaman
William E
WE
D000818:Animals; D000838:Anions; D001254:Astrocytoma / Q000378:metabolism / Q000382:microbiology; D001422:Bacterial Adhesion / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D016264:Dextran Sulfate / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000502:physiology; D006094:Gram-Positive Bacteria / Q000502:physiology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D007941:Leukemia P388; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010457:Peptidoglycan / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013682:Teichoic Acids / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000838:Anions; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C424124:TREM-2a receptor; C424125:TREM-2b receptor; D013682:Teichoic Acids; C447602:Trem3 protein, mouse; C009900:lipoteichoic acid; D016264:Dextran Sulfate