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The Effect of Human beta sub(2)-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant: Implications for peptide-based vaccines
The ability to directly load cell surface major histocompatibility complex (MHC) class I molecules with peptides provides a potentially powerful approach toward the development of vaccines to generate cell-mediated immunity. We demonstrate that exogenous beta sub(2)-microglobulin ( beta sub(2)m) sta...
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Published in: | The Journal of biological chemistry 1998-10, Vol.273 (43), p.28010-28018 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | The ability to directly load cell surface major histocompatibility complex (MHC) class I molecules with peptides provides a potentially powerful approach toward the development of vaccines to generate cell-mediated immunity. We demonstrate that exogenous beta sub(2)-microglobulin ( beta sub(2)m) stabilizes human cell surface MHC I molecules and facilitates their loading with exogenous peptides. Additionally, using three-dimensional crystal structures and known interaction sites between MHC I heavy chains and beta sub(2)m, we engineered variants of human beta sub(2)m (h beta sub(2)m) with a single serine substitution at residue 55. This alteration was predicted to promote hydrophobic interactions at the MHC I heavy chain/ beta sub(2)m interface and displace an ordered water molecule. Compared with h beta sub(2)m, the serine to valine substitution at residue 55 had improved ability to bind to cell surface HLA-A1, HLA-A2, and HLA-A3 molecules, facilitate exogenous peptide loading, and promote recognition by peptide-specific T cells. The inclusion of h beta sub(2)m or higher affinity variants when pulsing cells with MHC-restricted peptides increases the efficiency of peptide loading 50-80-fold. Therefore, the inclusion of h beta sub(2)m in peptide-based vaccines may increase cell surface antigen densities above thresholds that allow recognition of peptide antigens by the immune system, particularly for cryptic, subdominant, or marginally antigenic peptides. |
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ISSN: | 0021-9258 |