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

W J Venema, S Hiddingh, G M C Janssen, J Ossewaarde-van Norel, N Dam van Loon, J H de Boer, P A van Veelen, J J W Kuiper

Clinical immunology (Orlando, Fla.) 2023 Feb

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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. Copyright © 2022. Published by Elsevier Inc.

Citation

W J Venema, S Hiddingh, G M C Janssen, J Ossewaarde-van Norel, N Dam van Loon, J H de Boer, P A van Veelen, J J W Kuiper. Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis. Clinical immunology (Orlando, Fla.). 2023 Feb;247:109219