title: Novel CD8+ T cell antagonists based on beta 2-microglobulin.
abstract: The CD8 coreceptor of cytotoxic T lymphocytes binds to a conserved region of major histocompatibility complex class I molecules during recognition of peptide-major histocompatibility complex (MHC) class I antigens on the surface of target cells. This event is central to the activation of cytotoxic T lymphocyte (CTL) effector functions. The contribution of the MHC complex class I light chain, beta(2)-microglobulin, to CD8alphaalpha binding is relatively small and is mediated mainly through the lysine residue at position 58. Despite this, using molecular modeling, we predict that its mutation should have a dramatic effect on CD8alphaalpha binding. The predictions are confirmed using surface plasmon resonance binding studies and human CTL activation assays. Surprisingly, the charge-reversing mutation, Lys(58) --> Glu, enhances beta(2)m-MHC class I heavy chain interactions. This mutation also significantly reduces CD8alphaalpha binding and is a potent antagonist of CTL activation. These results suggest a novel approach to CTL-specific therapeutic immunosuppression.
authors.affiliation: Department of Chemistry, Central Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Vuidepot
authors.forename: Torben B
authors.initials: TB
authors.lastname: Andersen
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hutchinson
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Boulter
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
authors.forename: John I
authors.initials: JI
authors.lastname: Bell
authors.forename: W Graham
authors.initials: WG
authors.lastname: Richards
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016827:CD8 Antigens / Q000737:chemistry / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D020349:Surface Plasmon Resonance; D001613:beta 2-Microglobulin / Q000276:immunology*
chemical_list: D016827:CD8 Antigens; D015789:HLA-A2 Antigen; D001613:beta 2-Microglobulin