21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison's Disease Are Restricted by HLA-A2 and HLA-C7 Molecules

• Published in: Frontiers in immunology 2021-10, Vol.12, p.742848-742848
• Main Authors: Hellesen, Alexander, Aslaksen, Sigrid, Breivik, Lars, Røyrvik, Ellen Christine, Bruserud, Øyvind, Edvardsen, Kine, Brokstad, Karl Albert, Wolff, Anette Susanne Bøe, Husebye, Eystein Sverre, Bratland, Eirik
• Format: Article
• Language: English
• Subjects: 21-hydroxylase; Addison Disease - immunology; Addison’s disease; autoimmune; CD8+ T cells; CD8-Positive T-Lymphocytes - immunology; epitopes; Epitopes, T-Lymphocyte - immunology; HLA-A2 Antigen - immunology; HLA-C Antigens - immunology; Humans; Immunodominant Epitopes - immunology; Immunology; Steroid 21-Hydroxylase - immunology
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.742848

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 (21OH ), restricted by HLA-A2, and EPLARLEL (21OH ), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. 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. 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 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, 21OH , suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH ) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. 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.