Novel CD8+ T cell antagonists based on beta 2-microglobulin.
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.
Glick
Meir
M
Department of Chemistry, Central Chemistry Laboratory, University of Oxford, South Parks Road, Oxford, United Kingdom.
Price
David A
DA
Vuidepot
Anne-Lise
AL
Andersen
Torben B
TB
Hutchinson
Sarah L
SL
Laugel
Bruno
B
Sewell
Andrew K
AK
Boulter
Jonathan M
JM
Dunbar
P Rod
PR
Cerundolo
Vincenzo
V
Oxenius
Annette
A
Bell
John I
JI
Richards
W Graham
WG
Jakobsen
Bent K
BK
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*
D016827:CD8 Antigens; D015789:HLA-A2 Antigen; D001613:beta 2-Microglobulin