21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules
ObjectivesCD8+ 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-...
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.742848/full |
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| author | Alexander Hellesen Alexander Hellesen Sigrid Aslaksen Sigrid Aslaksen Lars Breivik Lars Breivik Lars Breivik Ellen Christine Røyrvik Ellen Christine Røyrvik Øyvind Bruserud Øyvind Bruserud Kine Edvardsen Karl Albert Brokstad Karl Albert Brokstad Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Eystein Sverre Husebye Eystein Sverre Husebye Eystein Sverre Husebye Eirik Bratland Eirik Bratland Eirik Bratland |
| author_facet | Alexander Hellesen Alexander Hellesen Sigrid Aslaksen Sigrid Aslaksen Lars Breivik Lars Breivik Lars Breivik Ellen Christine Røyrvik Ellen Christine Røyrvik Øyvind Bruserud Øyvind Bruserud Kine Edvardsen Karl Albert Brokstad Karl Albert Brokstad Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Eystein Sverre Husebye Eystein Sverre Husebye Eystein Sverre Husebye Eirik Bratland Eirik Bratland Eirik Bratland |
| author_sort | Alexander Hellesen |
| collection | DOAJ |
| description | ObjectivesCD8+ 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.MethodsRecombinant 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.ResultsWe 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.ConclusionWe 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. |
| first_indexed | 2024-12-17T20:04:09Z |
| format | Article |
| id | doaj.art-5a9c0773ab494ceeb083fa4b8ce83735 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T20:04:09Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5a9c0773ab494ceeb083fa4b8ce837352022-12-21T21:34:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.74284874284821-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 MoleculesAlexander Hellesen0Alexander Hellesen1Sigrid Aslaksen2Sigrid Aslaksen3Lars Breivik4Lars Breivik5Lars Breivik6Ellen Christine Røyrvik7Ellen Christine Røyrvik8Øyvind Bruserud9Øyvind Bruserud10Kine Edvardsen11Karl Albert Brokstad12Karl Albert Brokstad13Anette Susanne Bøe Wolff14Anette Susanne Bøe Wolff15Anette Susanne Bøe Wolff16Eystein Sverre Husebye17Eystein Sverre Husebye18Eystein Sverre Husebye19Eirik Bratland20Eirik Bratland21Eirik Bratland22Department of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Medicine, Haukeland University Hospital, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayBroegelmann Research Laboratory, University of Bergen, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Medicine, Haukeland University Hospital, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Medicine, Haukeland University Hospital, Bergen, NorwayDepartment of Clinical Science, University of Bergen, Bergen, NorwayKG Jebsen Centre for Autoimmune Diseases, University of Bergen, Bergen, NorwayDepartment of Medical Genetics, Haukeland University Hospital, Bergen, NorwayObjectivesCD8+ 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.MethodsRecombinant 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.ResultsWe 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.ConclusionWe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.742848/fullCD8+ T cells21-hydroxylaseautoimmuneAddison’s diseaseepitopes |
| spellingShingle | Alexander Hellesen Alexander Hellesen Sigrid Aslaksen Sigrid Aslaksen Lars Breivik Lars Breivik Lars Breivik Ellen Christine Røyrvik Ellen Christine Røyrvik Øyvind Bruserud Øyvind Bruserud Kine Edvardsen Karl Albert Brokstad Karl Albert Brokstad Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Anette Susanne Bøe Wolff Eystein Sverre Husebye Eystein Sverre Husebye Eystein Sverre Husebye Eirik Bratland Eirik Bratland Eirik Bratland 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules Frontiers in Immunology CD8+ T cells 21-hydroxylase autoimmune Addison’s disease epitopes |
| title | 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules |
| title_full | 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules |
| title_fullStr | 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules |
| title_full_unstemmed | 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules |
| title_short | 21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules |
| title_sort | 21 hydroxylase specific cd8 t cells in autoimmune addison s disease are restricted by hla a2 and hla c7 molecules |
| topic | CD8+ T cells 21-hydroxylase autoimmune Addison’s disease epitopes |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.742848/full |
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