Novel CD8+ T cell antagonists based on beta 2-microglobulin.
Glick M., Price DA., Vuidepot AL., Andersen TB., Hutchinson SL., Laugel B., Sewell AK., Boulter JM., Dunbar PR., Cerundolo V., Oxenius A., Bell JI., Richards WG., Jakobsen BK.
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.