Novel CD8+ T cell antagonists based on beta 2-microglobulin

The Journal of Biological Chemistry
Meir GlickBent K Jakobsen

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.

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Citations

May 31, 2007·The Journal of Experimental Medicine·Melissa L PrecopioRichard A Koup
Jan 21, 2004·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
Apr 17, 2003·The Journal of Biological Chemistry·Sarah L HutchinsonAndrew K Sewell
Oct 7, 2008·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Pratip K ChattopadhyayDavid A Price
Dec 30, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Giorgio ParmianiMario Santinami

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