MAIT cells frequency in the synovial fluid of psoriatic arthritis patients correlates with disease activity and show increased IL-17 production — ASN Events
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MAIT cells frequency in the synovial fluid of psoriatic arthritis patients correlates with disease activity and show increased IL-17 production (#120)

Ayako Kurioka 1 , Mohammed Hussein Al-Mossawi 2 , Emanuele Marchi 1 , Verity Hill 1 , Luzheng Xue 3 , Roy Pettipher 4 , Graham Ogg 3 5 , Paul Bowness 2 , Paul Klenerman 1
  1. Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
  2. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
  3. Oxford NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
  4. The Innovation Centre, Orca Pharmaceuticals Ltd, Abingdon, Oxford, United Kingdom
  5. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

Psoriatic arthritis (PsA) is an inflammatory joint disease that affects ~30% of psoriasis patients, associated with increased IL-17 expression. Mucosal associated invariant T-cells (MAIT) are a population of CD161++T-cells expressing the semi-invariant T-cell receptor Vα7.2-Jα33/Jα12/Jα20, restricted by the monomorphic MHC-related molecule 1, MR1. MAIT cells express RORγt and are the dominant producers of IL-17 within peripheral blood (PB) CD8+ T-cells, but their role in PsA has not been investigated in detail. Furthermore, the role of RORγt in the function of MAIT cells has not yet been probed before. 

In this study, we have performed an extensive analysis into the function of MAIT cells within synovial fluid (SF) from PsA patients. We found that MAIT cell frequency within SF varied between 1.9-60.5%, with a mean frequency of 13.83 ± 9.45% within CD8+ T-cells.  The frequency of SF MAIT cells correlated with the level of C-reactive protein (CRP) (R=0.69, p=0.020). Additionally, almost all MAIT cells in the SF expressed CD69 compared to paired PB samples. Importantly, there was a significant increase in the percentage of MAIT cells secreting IL-17 compared to paired PB samples. IL-17 production from MAIT cells, but not IFNγ, was inhibited in a dose-dependent manner by a RORγt-inhibitor developed by ORCA Pharmaceuticals. Furthermore, the RORγt-inhibitor blocked the expression of functional IL-23R by MAIT cells, but did not affect CD161, IL-12R, or IL-18R expression. Gene co-expression analysis of microarray data further confirmed that RORC expression is highly correlated with IL23R expression, while ZBTB16 overlaps with KLRB1 expression in MAIT cells.

Thus, we have shown that MAIT cell frequency in the joint is positively correlated with increased disease activity in PsA patients, and demonstrate that IL-17 production and IL-23R expression by MAIT cells can be inhibited by a novel RORγt-inhibitor, which has high therapeutic potential in treating autoimmune diseases including PsA.