A Positive-feedback Model for the Contribution of Virus-Specific T Cells to the Development of Rheumatoid Arthritis

Hendrik Nel¹, Pascale Wehr², Christopher Andoniou³, Iona Schuster³, Stephanie Gras⁴, Helen McGuire⁵, Helen Weedon⁶, Annabelle Small⁷, Katie Lowe⁷, Mariapia Degli-Esposti³, Mihir Wechalekar⁸ and Ranjeny Thomas⁹, ¹University of Queensland, Brisbane, Australia, Woolloongabba, Australia, ²University of Queensland Diamantina Institute, Brisbane, Australia, ³Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash, Australia, ⁴Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia, ⁵The University of Sydney, Charles Perkins Centre, Camperdown, Australia, ⁶Flinders University of South Australia, Bedford Park, Australia, ⁷Flinders University, Adelaide, Australia, ⁸Flinders Medical Centre, Bedford Park, Australia, ⁹University of Queensland, Brisbane, Australia

Meeting: ACR Convergence 2022

Keywords: Cytotoxic Cells, Mouse Models, RA, rheumatoid arthritis, T Cell

Session Information

Date: Sunday, November 13, 2022

Title: RA – Etiology and Pathogenesis Poster

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.

Disclosures: H. Nel, None; P. Wehr, None; C. Andoniou, None; I. Schuster, None; S. Gras, None; H. McGuire, None; H. Weedon, None; A. Small, None; K. Lowe, None; M. Degli-Esposti, None; M. Wechalekar, None; R. Thomas, Sandoz, CSL, Horizon Therapeutics, Janssen-Cilag.

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 .

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