title: Allele-specific recognition by LILRB3 and LILRA6 of a cytokeratin 8-associated ligand on necrotic glandular epithelial cells.
abstract: The LILRs are a family of receptors that regulate the activities of myelomonocytic cells. We found that specific allelic variants of two related members of the LILR family, LILRB3 and LILRA6, interact with a ligand exposed on necrotic glandular epithelial cells. The extracellular domains of LILRB3 and LILRA6 are very similar and their genes are highly polymorphic. A commonly occurring allele, LILRB3*12, displayed particularly strong binding of these necrotic cells and further screening of the products of LILRB3 alleles identified motifs that correlated with binding. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12, identified cytokeratins 8, 18 and 19. Purified proteins obtained from epithelial cell lysates, using anti-cytokeratin 8 antibodies, were able to activate LILRB3*12 reporter cells. Knock-down of cytokeratin 8 in epithelial cells abrogated expression of the LILRB3 ligand, while staining with recombinant LILRB3*12 showed co-localisation with cytokeratin 8 and 18 in permeabilised breast cancer cells. Necrosis is a common feature of tumours. The finding of a necrosis-associated ligand for these two receptors raises the possibility of a novel interaction that alters immune responses within the tumour microenvironment. Since LILRB3 and LILRA6 genes are highly polymorphic the interaction may influence an individual's immune response to tumours.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Des C
authors.initials: DC
authors.lastname: Jones
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Colin R A
authors.initials: CR
authors.lastname: Hewitt
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: María R
authors.initials: MR
authors.lastname: López-Álvarez
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Jahnke
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Alasdair I
authors.initials: AI
authors.lastname: Russell
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Radjabova
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Alice R Z
authors.initials: AR
authors.lastname: Trowsdale
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053533:Keratin-8 / Q000378:metabolism*; D009336:Necrosis / Q000276:immunology / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D053533:Keratin-8; C586909:LILRA6 protein, human; C527699:LILRB3 protein, human; D011971:Receptors, Immunologic
keywords: DAMP; LILR; breast cancer; cytokeratin; immune escape