Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2023-02, Vol.247, p.109219-109219, Article 109219
• Main Authors: Venema, W.J., Hiddingh, S., Janssen, G.M.C., Ossewaarde-van Norel, J., van Loon, N. Dam, de Boer, J.H., van Veelen, P.A., Kuiper, J.J.W.
• Format: Article
• Language: English
• Subjects: Aminopeptidases; Arrestin; Autoantigens; Birdshot Chorioretinopathy; CD8-Positive T-Lymphocytes; Chorioretinitis; HLA-A Antigens; Humans; Minor Histocompatibility Antigens; Peptides - metabolism; Retina
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2022.109219

HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified. The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls. We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls. We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients. Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG. •Peptides from retinal arrestin (SAG) are natural ligands of HLA-A29 in cell lines from birdshot chorioretinitis patients.•ERAP aminopeptidases can generate SAG-derived peptides by trimming precursor peptides.•CD8+ T cells reactive to SAG peptides in complex with HLA-A29 are not detected in blood or eye biopsies of patients.