High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

被引：9

作者：

Moysey, Ruth K. ^{[1
]}

Li, Yi ^{[1
]}

Paston, Samantha J. ^{[1
]}

Baston, Emma E. ^{[1
]}

Sami, Malkit S. ^{[1
]}

Cameron, Brian J. ^{[1
]}

Gavarret, Jessie ^{[1
]}

Todorov, Penio ^{[1
]}

Vuidepot, Annelise ^{[1
]}

Dunn, Steven M. ^{[1
]}

Pumphrey, Nicholas J. ^{[1
]}

Adams, Katherine J. ^{[1
]}

Yuan, Fang ^{[1
]}

Dennis, Rebecca E. ^{[1
]}

Sutton, Deborah H. ^{[1
]}

Johnson, Andy D. ^{[1
]}

Brewer, Joanna E. ^{[1
]}

Ashfield, Rebecca ^{[1
]}

Lissin, Nikolai M. ^{[1
]}

Jakobsen, Bent K. ^{[1
]}

机构：

[1] Immunocore Ltd, Abingdon OX14 4RX, Oxon, England

来源：

PROTEIN & CELL | 2010年 / 1卷 / 12期

关键词：

CD8(+) T cells; cellular activation; autoimmunity; cell surface molecules; binding affinity; phage display;

D O I：

10.1007/s13238-010-0144-5

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin superfamily 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 sub-nanomolar 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.

引用

页码：1118 / 1127

页数：10

共 37 条

[1] Assessment of CD8 involvement in T cell clone avidity by direct measurement of HLA-A2/Mage3 complex density using a high-affinity TCR like monoclonal antibody [J].