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- W4313385498 abstract "Abstract Central tolerance imposed during thymic development and mechanisms of peripheral tolerance result in a mature T cell repertoire capable of cross-reacting weakly on self, but usually incapable of activation. We have observed mutations in class I heavy chains capable of activating normally tolerant T cells which can then cross-react effectively on self. We hypothesized that mutation of the class I heavy chain, based on our understanding of MHC fine structure, could be used to generate engineered MHC molecules capable of activating T cells normally incapable of activation due to self-tolerance that could then cross-react effectively on self, but without altering the presentation of bound peptides. Known ternary complex (pMHC:TCR) crystal structures were modeled to predict amino acid substitutions within the class I heavy chain resulting in increased stable contacts between pMHC and TCR without altering the structure of bound peptides. Four substitutions within the class I heavy chain meeting these criteria were predicted by the structure based modeling. Cell lines were established which demonstrated stable surface expression of the engineered class I molecules. In a direct test of binding, a single chain TCR was detected with 20 fold greater intensity on the surface of cells expressing engineered MHC molecules compared with wild-type MHC, while competitive inhibition of binding a labeled peptide demonstrated unaltered peptide presentation. Stimulation of T cells with a weak antigen presented by the engineered MHC resulted in enhanced activation and proliferation compared with wild-type MHC. In an in vivo transplant model, protective immunity was induced against a native tumor after challenge with tumor expressing engineered MHC." @default.
- W4313385498 created "2023-01-06" @default.
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- W4313385498 date "2016-05-01" @default.
- W4313385498 modified "2023-10-16" @default.
- W4313385498 title "Engineering MHC class I fine structure for activation of self-tolerant T cells" @default.
- W4313385498 doi "https://doi.org/10.4049/jimmunol.196.supp.116.17" @default.
- W4313385498 hasPublicationYear "2016" @default.
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