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dc.contributor.authorHellesen, Alexander
dc.contributor.authorAslaksen, Sigrid
dc.contributor.authorBreivik, Lars Ertesvåg
dc.contributor.authorRøyrvik, Ellen Christine
dc.contributor.authorBruserud, Øyvind
dc.contributor.authorEdvardsen, Kine Susann Waade
dc.contributor.authorBrokstad, Karl Albert
dc.contributor.authorWolff, Anette Susanne Bøe
dc.contributor.authorHusebye, Eystein Sverre
dc.contributor.authorBratland, Eirik
dc.description.abstractObjectives: CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison’s disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. Methods: Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH. Results: We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. Conclusion: We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.en_US
dc.publisherFrontiers Mediaen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.title21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Moleculesen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.rights.holderCopyright 2021 Hellesen, Aslaksen, Breivik, Røyrvik, Bruserud, Edvardsen, Brokstad, Wolff, Husebye and Bratlanden_US
dc.source.journalFrontiers in Immunologyen_US
dc.relation.projectNorges forskningsråd: 262677en_US
dc.identifier.citationFrontiers in Immunology. 2021, 12, 742848.en_US

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