Mucosal-associated Invariant T cells activation and Il-17 expression characterize the synovial fluid and peripheral blood of patients with psoriatic arthritis and are modulated by Tofacitinib

Background:
One of the key players in autoimmune arthritis is T-cells. Both CD4+ and CD8+ T-cells have been implicated in mediating many aspects of synovial inflammation [1,2]. Oligoclonal populations of CD8+ T-cells specific for epitopes from Epstein-Barr virus, cytomegalovirus, and influenza virus were found enriched in the synovial fluid of patients with inflammatory arthritis [3]. There are also data suggesting that CD4+ T-cells from the inflamed synovium in rheumatoid arthritis (RA) represent activated Th1 cells that secrete IFNγ, which in turn orchestrates synovial inflammation [4–6]. Among CD4+ T-cells, regulatory T-cells (Treg), which are crucial in preserving immune homeostasis, are believed to be dysfunctional in autoimmunity. In the inflamed joints of juvenile idiopathic arthritis (JIA) patients, a higher frequency of clonally expanded Tregs was observed than conventional CD4+ T-cells [7].
Objectives:
• Mapping the immune phenotypes in synovial fluid of juvenile and adult patients with chronic autoimmune arthritis.
• Decoding the synovial fluid T-cell receptor repertoire across different arthritis groups and T-cell subsets.
• Identifying T-cell receptors specific to HLA-B27 associated spondyloarthropathies.
Methods:
27 patients were recruited: 6 had oligoarticular JIA (oJIA), 4 had enthesitis-related JIA (JIA-ERA), 3 had juvenile psoriatic arthritis (JIA-PsA), 5 had adult psoriatic arthritis (PsA), 5 had RA, 3 had Lyme arthritis (borrelia), and 1 had spondyloarthritis (SpA). Their synovial fluid was collected and processed into mononuclear cells (SFMC). Single-cell RNA-seq and TCR-seq were performed on the SFMC. Bulk TCR-seq was done on the CD4+, CD8+, and Treg fractions.
Results:
Our single-cell sequencing data indicate that among the 28 identified cell phenotypes, Th1/Th17 cells were the dominant population among all patient groups, having the highest proportion out of the total T-cell count in JIA-ERA (Figure 1A). Furthermore, compared to B27– patients, B27+ patients had upregulated HLA-DP, HLA-DQ, HLA-DR, and GZMA genes in central memory CD8+ T-cells, implying an increase in T-cell activation and cytotoxic activity (Figure 1B). Gene set enrichment analysis also suggests pro-inflammatory pathways (e.g., TNFα, IFNα, and IFNγ signalling), and T-cell activation in response to viruses in B27+ patients.
From the bulk TCRβ sequencing data (Figure 2), we observed that HLA-B27+ patients shared broad TCRBV20 clusters specific for various viral epitopes, indicating a possible cross-reactive response. Furthermore, this method highlighted TCR clusters with sequence similarity to those known to be associated with HLA-B27 pathologies, as well as TCRs with unknown specificity, but a conserved GRGR motiflet.
Conclusion:
The findings in this study provide insights into how TCR repertoires differ between arthritis groups, patients’ ages, T-cell subsets, and whether viral/bacterial infection contributes to arthritis onset and flares. Such knowledge will greatly contribute to the understanding of T-cells’ and TCRs’ participation in the underlying pathophysiology of arthritis.