Session Type: Poster Session B
Session Time: 9:00AM-10:30AM
Background/Purpose: Rheumatoid Arthritis (RA) is associated with specific HLA-DR genotypes with an emphasis on the role of CD4+ effector-memory T cells (Tem) in disease pathogenesis. However, single cell sequencing technologies identified large numbers of CD8+ cytotoxic T lymphocytes (CTL) with distinct granzyme expression profiles infiltrating RA synovial tissue (ST) in active, established RA. Here we assessed T cell clonotypes in ST and peripheral blood (PB) of patients with recent-onset untreated RA and addressed the contribution of virus-specific CD8+ T cells to development of antigen-induced inflammatory arthritis
Methods: Synovial tissues (ST) and paired PBMC from 4 DMARD-naïve recent-onset RA patients were assessed by combined single-cell RNA/TCR-Seq (10x Genomics Chromium 5’ platform) to determine clonal-specific T cell signatures. Models of Ovalbumin (OVA)-induced arthritis (AIA) were established in mice with murine cytomegalovirus (mCMV) latent infection or acute, resolved lymphocytic choriomeningitis virus (LCMV) infection. AIA footpad swelling, OVA- and virus-specific (tetramer+) T cell phenotypes, and functional responses to antigen-restimulation were assessed
Results: A large proportion of T cells in PBMC and ST of all RA patients had signatures of polyfunctional CD4 or CD8 CTL expressing TNF, IFNG, GZMK, GZMA and GZMB. Clonally-expanded TCR sequences from all donors included those predicted to be directed towards HLA class I-restricted CMV or EBV epitopes with 100% sequence identity. CMV epitope-specificity of a TCR sequence shared in PB and ST was confirmed with a CMV-specific tetramer. Imaging mass cytometry of ST identified perivascular clonotypic GZB+ CD8+ T cells, adjacent to DCs, monocytes and thy1+ fibroblasts. In mice with latent mCMV, OVA-AIA was more severe. OVA-specific and host bystander KLRG1- central-memory T cells and mCMV-specific and host bystander PD1+KLRG1- effector-memory CTL were expanded in popliteal draining lymph nodes compared to uninfected OVA-AIA mice. CD4+ and CD8+ T cells produced more IFN-g and TNF in response to OVA and mCMV-IE1 peptide respectively, in infected compared to uninfected mice. After recovering from acute LCMV, AIA was more severe and LCMV-specific CTL produced more cytokine, but the phenotype of OVA- and LCMV-specific and host T cells was unchanged
Conclusion: These findings suggest a model in which positive feedback from arthritogenic or viral CD4+ T cells to antigen-presenting cells (APC) carrying residual latent viral antigen enhances host CD4+ and CD8+ bystander autoreactive memory along with viral antigen-specific CTL expansion, TNF and IFN-g production. In RA, latent-virus-specific CD4+ and CD8+ CTL could contribute to inflammation and activation or lysis of APC targets, thus propagating autoimmunity.
To cite this abstract in AMA style:Nel H, Wehr P, Andoniou C, Schuster I, Gras S, McGuire H, Weedon H, Small A, Lowe K, Degli-Esposti M, Wechalekar M, Thomas R. A Positive-feedback Model for the Contribution of Virus-Specific T Cells to the Development of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/a-positive-feedback-model-for-the-contribution-of-virus-specific-t-cells-to-the-development-of-rheumatoid-arthritis/. Accessed .
« Back to ACR Convergence 2022
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-positive-feedback-model-for-the-contribution-of-virus-specific-t-cells-to-the-development-of-rheumatoid-arthritis/