title: HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding.
abstract: Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded β(2)-microglobulin-associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.
authors.affiliation: Immunology Division, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom. dcj28@cam.ac.uk
authors.forename: Des C
authors.initials: DC
authors.lastname: Jones
authors.forename: Vasilis
authors.initials: V
authors.lastname: Kosmoliaptsis
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lapaque
authors.forename: Isobel
authors.initials: I
authors.lastname: Smith
authors.forename: Azumi
authors.initials: A
authors.lastname: Kono
authors.forename: Chiwen
authors.initials: C
authors.lastname: Chang
authors.forename: Louise H
authors.initials: LH
authors.lastname: Boyle
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Taylor
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Allen
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D005805:Genes, MHC Class I / Q000276:immunology*; D057809:HEK293 Cells; D006680:HLA Antigens / Q000235:genetics*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D017510:Protein Folding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; C530062:LILRA3 protein, human; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D001613:beta 2-Microglobulin; C413086:leukocyte-immunoglobulin--like receptor 6