Autoreactive T cells identified in patients with anti-Jo1+ antisynthetase syndrome recognise a new epitope on histidyl t-RNA synthetase.
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Galindo-Feria AS, Sharma RK, Dubnovitsky A, Gerstner C, Kozhukh G, Van Vollenhoven A, Boada JSD, Ramsköld D, Achour A, Dastmalchi M, Reid HH, Sandalova T, Rossjohn J, Chemin K, Malmström V, Lundberg IE, Horuluoglu B
Ann. Rheum. Dis. - (-) - [2025-10-25; online 2025-10-25]
Anti-Jo1+ antisynthetase syndrome (ASyS) is characterised by autoantibodies targeting histidyl t-RNA synthetase (HisRS), association with HLA-DRB1*03:01 and a distinct clinical phenotype including interstitial lung disease, myositis, arthritis, and mechanic's hands. Previous studies of autoreactive HisRS-specific CD4+T cells point to yet undiscovered T cell epitopes. We aimed to identify new epitopes on HisRS to investigate the presence of autoreactive T cells and their corresponding T-cell receptor (TCR) repertoire from patients with ASyS. Peptides from HisRS N-terminal region with appropriate major histocompatibility complex (MHC) anchor residues were selected for in vitro binding assays. The peptide (HisRS41-55) with the highest HLA-DRB1*03:01 binding affinity was selected for studies with HLA-class II tetramers. Peripheral blood mononuclear cells (PBMCs) from patients with ASyS with HLA-DRB1*03:01 (n = 12) were stimulated in vitro with peptide and peptide-HLA-DRB1*03:01 tetramers were used to detect HisRS+CD4+T cells. Single TCR sequencing of captured T cells allowed analyses of the underlying TCR repertoire. We identified a new T cell epitope on HisRS with high affinity for HLA-DRB1*03:01. Autoreactive HisRS+CD4+T cells were detected in PBMCs of patients (n = 6/12). TCR repertoire analysis of HisRS+CD4+T cells revealed shared gene V-alpha and beta usages. Moreover, HisRS+CD4+T cells persisted after treatment in 2 patients (P2 and P4) and 2 identical T cell clones were detected between the initial and follow-up time points in 1 patient (P2). Autoreactive T-cells targeting a new HisRS epitope were identified indicating T cell reactivity to diverse epitopes of the HisRS protein in patients with anti-Jo1 autoantibodies. Furthermore, we demonstrated the TCR repertoire of autoreactive HisRS+CD4+T cells in patients. Persistence of these T-cells and specific clones may be contributing to disease.
NGI Stockholm (Genomics Applications) [Service]
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41139557
DOI 10.1016/j.ard.2025.09.015
Crossref 10.1016/j.ard.2025.09.015
pii: S0003-4967(25)04429-2