High affinity soluble ILT2 receptor: a potent inhibitor of CD8(+) T cell activation.
10.1007/s13238-010-0144-5
- Author:
Ruth K MOYSEY
1
;
Yi LI
;
Samantha J PASTON
;
Emma E BASTON
;
Malkit S SAMI
;
Brian J CAMERON
;
Jessie GAVARRET
;
Penio TODOROV
;
Annelise VUIDEPOT
;
Steven M DUNN
;
Nicholas J PUMPHREY
;
Katherine J ADAMS
;
Fang YUAN
;
Rebecca E DENNIS
;
Deborah H SUTTON
;
Andy D JOHNSON
;
Joanna E BREWER
;
Rebecca ASHFIELD
;
Nikolai M LISSIN
;
Bent K JAKOBSEN
Author Information
1. Immunocore Limited, 57c Milton Park, Abingdon, Oxon, OX14 4RX, UK.
- Publication Type:Journal Article
- MeSH:
Amino Acid Sequence;
Antigens, CD;
chemistry;
genetics;
pharmacology;
Autoimmunity;
Biological Assay;
Cell Line;
Cytotoxicity, Immunologic;
genetics;
immunology;
Dose-Response Relationship, Immunologic;
Humans;
Immunoglobulins;
immunology;
metabolism;
Immunologic Factors;
chemistry;
genetics;
pharmacology;
Kinetics;
Leukocyte Immunoglobulin-like Receptor B1;
Lymphocyte Activation;
genetics;
immunology;
Major Histocompatibility Complex;
genetics;
immunology;
Molecular Sequence Data;
Molecular Targeted Therapy;
Mutagenesis, Site-Directed;
Peptide Library;
Polyethylene Glycols;
Protein Binding;
genetics;
immunology;
Receptors, Immunologic;
chemistry;
genetics;
Recombinant Fusion Proteins;
genetics;
metabolism;
T-Lymphocytes, Cytotoxic;
immunology;
metabolism
- From:
Protein & Cell
2010;1(12):1118-1127
- CountryChina
- Language:English
-
Abstract:
Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.
