Identification of multiple potent binding sites for human leukocyte associated Ig-like receptor LAIR on collagens II and III.
Immune responses are tightly controlled by the opposing actions of activating and inhibitory immune receptors. Previously we identified collagens as ligands for the inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1), revealing a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix collagens. This interaction can be blocked by LAIR-2, a secreted member of the LAIR-1 family. LAIR-1 specifically interacts with synthetic trimeric peptides containing 10 repeats of glycine-proline-hydroxyproline (GPO) residues which can directly inhibit immune cell activation in vitro. Here we studied the interaction of human LAIR-1 and LAIR-2 with collagen in more detail by using novel overlapping synthetic trimeric peptides (Toolkits) encompassing the entire triple-helical domain of human collagens II and III. LAIR-1 and LAIR-2 bind several of these collagen-like peptides, with LAIR-2 being able to bind more than LAIR-1. LAIR binding to trimeric collagen peptides was influenced by GPO content of the peptide, although additional non-GPO triplets contributed to the interaction. Furthermore, we identified several trimeric peptides that were potent LAIR-1 ligands and could efficiently induce inhibition of T cell activation and FceRI-induced degranulation of RBL-2H3 cells through binding to LAIR-1. A detailed understanding of the LAIR recognition motifs within collagen may lead to the development of potent reagents that can be used in in vitro, ex vivo, and in vivo functional studies to dissect the biology and function of the collagen/LAIR-1 interaction.
Lebbink
Robert Jan
RJ
Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Raynal
Nicolas
N
de Ruiter
Talitha
T
Bihan
Dominique G
DG
Farndale
Richard W
RW
Meyaard
Linde
L
D000595:Amino Acid Sequence; D000818:Animals; D015549:Basophil Degranulation Test; D001665:Binding Sites; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D024043:Collagen Type II / Q000378:metabolism*; D024061:Collagen Type III / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D024043:Collagen Type II; D024061:Collagen Type III; C431503:LAIR-2 receptor; D050778:NFATC Transcription Factors; D010446:Peptide Fragments; D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C108073:leukocyte-associated immunoglobulin-like receptor 1; C098341:platelet membrane glycoprotein VI