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dc.contributor.authorHasenkrug, Kim J.
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 52-01, Section: B, page: 2500.;Advisors: Stanley G. Nathenson.
dc.description.abstractClass I gene products of the Major Histocompatibility Complex (MHC) serve as recognition elements for the immune system by binding to peptides processed from intracellular proteins and presenting them to cytolytic T-lymphocytes (CTL). When the presented peptide is derived from a virus or other foreign protein, CTL are activated to lyse the infected cell. CTL recognition of MHC products also mediates tissue transplant rejections. An MHC class I mutant, B10.sm1, was discovered by loss of reactivity to monoclonal antibodies, and it has a unique genotype and phenotype. This thesis describes the characterization of the sm1 mutation at the molecular level, and various aspects of the sm1 phenotype including its serology, biochemistry, immunology and cell biology. Cells from B10.sm1 mice are non-reactive with antibodies specific for the H-2K{dollar}\sp{lcub}\rm S{rcub}{dollar} class I product due to a single A to T transversion at position 392, translating to an Arg to Trp substitution at amino acid107. Pulse-chase and surface labeling experiments showed that a major effect of the 107 substitution was a time dependent dissociation between heavy and light chains although 107 does not appear to be a light chain contact residue. The ability of newly synthesized heavy chains to dimerize with B2m is consistent with data suggesting the presence of a chaperonin-like molecule that promotes and stabilizes proper folding and assembly in the endoplasmic reticulum. Although normal levels of heavy chains were detected on sm1 cell surfaces, only about 20% were light chain associated. Antibody detectable surface expression in mutant cells is temperature sensitive, and wild type levels of antibody epitopes were induced by overnight incubations at 25{dollar}\sp\prime{dollar}C. This induction was not accompanied by an increase in heavy/light chain dimers and was likely the result of the stabilization of native conformation in existing heterodimers that are thermally labile at 37{dollar}\sp\prime{dollar}C. Reciprocal skin grafts between B10.sm1 and B10.S were rejected and the rejections were mediated by CD8+ T-cells. Although mutant molecules were not recognized by antibodies at 37{dollar}\sp\prime{dollar}C, they were recognized by K{dollar}\sp{lcub}\rm S{rcub}{dollar} specific allo-CTL.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titleThe discovery and characterization of a unique MHC class I in vivo mutant, B10.sm1

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