Autoantigen-specific CD8+ T-cell signature in rheumatoid arthritis 4241

Abstract Description A hallmark of rheumatoid arthritis (RA) disease is the infiltration of immune cells, with recent evidence suggesting a role for CD8 T-cells, yet limited knowledge exists on their epitope specificity and role in disease development. Here, we comprehensively analyzed CD8 T-cell recognition towards 400 in silico predicted self-peptide epitopes in native and citrullinated form using state-of-the art cytometry-based DNA-barcoded peptide-MHC (pMHC) multimer techniques in a cohort of 40 RA patients and 17 healthy donors (HD). Subsequent single-cell sequencing (sc-seq), TCR- sequencing of biopsies and Cas9 mediated TCR knock-ins extended and confirmed the results. The pMHC barcoding screen established a clear pattern of immune recognition, revealing CD8+ T cell responses targeting 51 unique epitopes mainly stemming from collagen, fibrinogen and aggrecan. Interestingly, citrullinated peptide epitopes were highly immunogenic and the position of the citrullination within the peptide binding groove of the pMHC complex seemed to determine if these epitopes could be cross-recognized in their native form. Sc-seq confirmed epitope candidates and revealed a RA-specific TCR clonotype landscape that was conserved longitudinally with differences in phenotype and gene expression patterns mainly driven by clonotype identity. Here, we demonstrate the epitope-specificity and clonality of the RA-specific CD8 T cell pool in RA patients vs HD, thus paving the way for future targeted CD8 T-cell therapies. Funding Sources This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie-Sklodowska-Curie grant agreement No 899987 Topic Categories Basic Autoimmunity (BA)