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The Journal of Immunology, 2005, 174: 2116-2123.
Copyright © 2005 by The American Association of Immunologists

Membrane-Anchored {beta}2-Microglobulin Stabilizes a Highly Receptive State of MHC Class I Molecules1

Dikla Berko*,{dagger}, Yaron Carmi*, Gal Cafri*, Shimrit Ben-Zaken*,{ddagger}, Helena Migalovich Sheikhet§, Esther Tzehoval§, Lea Eisenbach§, Alon Margalit*,{ddagger} and Gideon Gross2,*,{ddagger}

* Laboratory of Immunology, MIGAL-Galilee Technology Center, Kiryat Shmona, Israel; {dagger} Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel; {ddagger} Department of Biotechnology, Tel-Hai Academic College, Upper Galilee, Israel; and § Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

The magnitude of response elicited by CTL-inducing vaccines correlates with the density of MHC class I (MHC-I)-peptide complexes formed on the APC membrane. The MHC-I L chain, {beta}2-microglobulin ({beta}2m), governs complex stability. We reasoned that genetically converting {beta}2m into an integral membrane protein should exert a marked stabilizing effect on the resulting MHC-I molecules and enhance vaccine efficacy. In the present study, we show that expression of membranal human {beta}2m (h{beta}2m) in mouse RMA-S cells elevates MHC-I thermal stability. RMA-S transfectants bind an exogenous peptide at concentrations 104- to 106-fold lower than parental RMA-S, as detected by complex-specific Abs and by T cell activation. Moreover, saturation of the transfectants’ MHC-I by exogenous peptide occurs within 1 min, as compared with ~1 h required for parental cells. At saturation, however, level of peptide bound by modified cells is only 3- to 5-fold higher. Expression of native h{beta}2m only results in marginal effect on the binding profile. Soluble {beta}2m has no effect on the accelerated kinetics, but the kinetics of transfectants parallel that of parental cells in the presence of Abs to h{beta}2m. Ab inhibition and coimmunoprecipitation analyses suggest that both prolonged persistence of peptide-receptive H chain/{beta}2m heterodimers and fast heterodimer formation via lateral diffusion may contribute to stabilization. In vivo, peptide-loaded transfectants are considerably superior to parental cells in suppressing tumor growth. Our findings support the role of an allosteric mechanism in determining ternary MHC-I complex stability and propose membranal {beta}2m as a novel scaffold for CTL induction.




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A. Margalit, H. M. Sheikhet, Y. Carmi, D. Berko, E. Tzehoval, L. Eisenbach, and G. Gross
Induction of Antitumor Immunity by CTL Epitopes Genetically Linked to Membrane-Anchored {beta}2-Microglobulin
J. Immunol., January 1, 2006; 176(1): 217 - 224.
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