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J Biol Chem, Vol. 273, Issue 43, 28010-28018, October 23, 1998

The Effect of Human ₂-Microglobulin on Major Histocompatibility Complex I Peptide Loading and the Engineering of a High Affinity Variant
IMPLICATIONS FOR PEPTIDE-BASED VACCINES

Michael J. Shields, Ryuji Kubota^¶, Wesley Hodgson, Steven Jacobson^¶, William E. Biddison^¶, and Randall K. Ribaudo

From the  Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892-1152 and the ^¶ Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892

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 ₂-microglobulin (₂m) 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 ₂m, we engineered variants of human ₂m (h₂m) with a single serine substitution at residue 55. This alteration was predicted to promote hydrophobic interactions at the MHC I heavy chain/₂m interface and displace an ordered water molecule. Compared with h₂m, 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 h₂m or higher affinity variants when pulsing cells with MHC-restricted peptides increases the efficiency of peptide loading 50-80-fold. Therefore, the inclusion of h₂m 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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