The Journal of Immunology, Vol 155, Issue 7 3481-3493, Copyright © 1995 by American Association of Immunologists

ARTICLES

Polymorphism at position nine of the MHC class I heavy chain affects the stability of association with beta 2-microglobulin and presentation of a viral peptide

RK Ribaudo and DH Margulies
Molecular Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

To identify residues that control the interactions between MHC-heavy chains and (beta 2m) sequence comparisons were made between murine class I MHC molecules with high (H-2Dd, H-2Kb) and low (H-2Ld, H-2Db) affinities for beta 2m. A single residue at position 9 was evaluated for its contribution to the stability of the complex. Mutagenesis of the glutamic acid at position 9 of H-2Ld to valine, as is found in H- 2Dd and H-2Kb, resulted in both qualitative and quantitative effects on inter-chain interactions, intracellular transport, peptide binding, and peptide presentation. In in vitro translation and assembly studies, the E9V mutation resulted in a more stable association of beta 2m with the heavy chain after immunoprecipitation with the alpha 2 domain-specific Ab 30-5-7 in the presence of an H-2Ld-restricted peptide. E9V variant expressed in transfected L cells had similar surface expression compared with H-2Ld despite exhibiting a slower rate of maturation. However, cells expressing E9V were unable to present peptide Ag to a specific T cell hybridoma. H-2LdE9V in E-3 cells, which are defective in TAP-dependent peptide transport, was expressed at higher levels than H-2Ld and was stabilized more efficiently by the addition of exogenous human beta 2m. Thus, amino acid position 9 not only plays an important role in the interaction of the MHC-1 molecule with the beta 2m, it also qualitatively and quantitatively influences peptide binding and Ag presentation.

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