title: Leukocyte Ig-Like receptor B1 restrains dendritic cell function through increased expression of the NF-κB regulator ABIN1/TNIP1.
abstract: Inhibitory receptors of the human leukocyte immunoglobulin-like receptor family are constitutively expressed on all myeloid cell types and regulate their functional activity. We demonstrate that ligation of the human leukocyte antigen class I-specific receptor LILRB1, during the differentiation of monocytes to dendritic cells in vitro, results in increased expression of the nuclear factor κB inhibitor protein ABIN1 (also known as TNIP1). Similarly increased expression of ABIN1/TNIP1 was observed in the "immunosuppressive" monocyte populations of patients with non-Hodgkin lymphoma ex vivo. Reducing expression of ABIN1/TNIP1 using small interfering ribonucleic acid allows dendritic cells and immunosuppressive monocytes to respond to stimulation by allowing nuclear factor κB translocation to the nucleus (P < 0.001), increasing cell surface expression of antigen presentation and costimulatory molecules (P < 0.01), increasing phagocytic capacity (P < 0.001), secreting proinflammatory cytokines (P < 0.01), and an increasing ability to stimulate T cell responses (P < 0.05). Our study, therefore, identifies an important functional role for ABIN1/TNIP1 in mediating the effects of LILRB1 ligation-induced inhibitory effects on immune responses. Our findings suggest that inhibiting the LILRB1-ABIN1/TNIP1 pathway in antigen-presenting cells could be a therapeutic approach to stimulate antitumor immune responses. Conversely, stimulation of the pathway may also ameliorate autoimmune diseases in which TNIP1 is a susceptibility gene.
authors.affiliation: Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom; rahul47@live.com.
authors.forename: Rahul C
authors.initials: RC
authors.lastname: Khanolkar
authors.affiliation: Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Michail
authors.initials: M
authors.lastname: Kalogeropoulos
authors.affiliation: Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Alistair
authors.initials: A
authors.lastname: Lawrie
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; and Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Ali
authors.initials: A
authors.lastname: Roghanian
authors.affiliation: Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Vickers
authors.affiliation: Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Young
mesh_terms: D017951:Antigen Presentation; D015703:Antigens, CD / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008228:Lymphoma, Non-Hodgkin / Q000097:blood; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D038042:Myelopoiesis / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010587:Phagocytosis; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C117046:TNIP1 protein, human; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: DC maturation; LILRB1; immunosuppression; inhibitory receptor; lymphoma