Novel CD8 super(+) T Cell Antagonists Based on beta sub(2)-Microglobulin

• Published in: The Journal of biological chemistry Vol. 277; no. 23; pp. 20840 - 20846
• Main Authors: Glick, M, Price, DA, Vuidepot, A, Andersen, T B, Hutchinson, S L, Laugel, B, Sewell, A K, Boulter, J M, Dunbar, PR, Cerundolo, V, Oxenius, A, Bell, JI, Richards, W G, Jakobsen, B K
• Format: Journal Article
• Language: English
• Published: 07.06.2002
• Subjects: b2-microglobulin; CD8 antigen
• ISSN: 0021-9258

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 sub(2)-microglobulin, to CD8 alpha alpha 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 CD8 alpha alpha binding. The predictions are confirmed using surface plasmon resonance binding studies and human CTL activation assays. Surprisingly, the charge-reversing mutation, Lys super(58) arrow right Glu, enhances beta sub(2)m-MHC class I heavy chain interactions. This mutation also significantly reduces CD8 alpha alpha binding and is a potent antagonist of CTL activation. These results suggest a novel approach to CTL-specific therapeutic immunosuppression.