Mucosal-Associated Invariant T Cells Are an Important Source of TNF in Rheumatoid Arthritis

Diahann Jansen¹, Elizabeth Klinken¹, Hendrik Nel¹, Soi Cheng Law¹, Hester Koppejan², Marjolijn Hameetman³, Ligong Liu⁴, Alexandra Corbett⁵, Sidonia Eckle⁵, David Fairlie⁴, Rene E.M. Toes⁶, Floris van Gaalen⁷, Jamie Rossjohn^8,9,10, James McCluskey⁵ and Ranjeny Thomas¹, ¹The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Australia, ²Department of Rheumatology, Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ³Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁴Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia, ⁵Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia, ⁶Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁷Rheumatology, Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁸Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia, ⁹Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom, ¹⁰Infection and Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: cytokines, rheumatoid arthritis (RA) and tumor necrosis factor (TNF), T cells

Session Information

Date: Tuesday, November 7, 2017

Title: T Cell Biology and Targets in Autoimmune Disease Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: CD8+ T cells have been described to comprise up to 40% of the rheumatoid arthritis (RA) synovial T cell compartment but their pathogenic function is largely unknown. Mucosal associated invariant T (MAIT) cells are predominantly CD4-CD8+ innate-like lymphocytes which comprise up to 10% of circulating T cells and enter mucosal sites. They express a semi-invariant T cell receptor restricted to the MHC class I-like molecule, MR1. MR1 presents ligands derived from the riboflavin synthesis pathway, common to a range of bacteria and yeast. There is evidence for oral and gastrointestinal microbial dysbiosis in RA, and the majority of abundant bacterial species in RA patients are capable of riboflavin synthesis. However, the mechanisms underlying these disease associations are unclear. Furthermore, TNF is both an effector cytokine produced by activated MAIT cells and a key cytokine driver of RA. Therefore, we investigated the relationship between MAIT cells and TNF response to the riboflavin ligand 5-OPRU in RA patients and healthy controls (HC).

Methods: We identified the proportion of MAIT cells based on the expression of CD3, CD4, CD161 and TRAV1-2 or positivity for MR1-5-OPRU tetramers using flow cytometry in peripheral blood (PB) of 14 RA patients and 12 HC and synovial fluid of 8 RA patients. We analysed cellular activation of MAIT cells after stimulation with 5-OPRU by defining the expression of activation markers CD25 and CD69 and the production of TNF and IFN-gamma.

Results: MAIT cells comprised 0.5-17.5% of the CD4-CD3+ T cells in RA PB. MR1-tetramer+ MAIT cell frequencies in PB of HC and RA patients were comparable and on average 85% of MAIT cells were CD4 negative. CD161 expression decreased after MAIT cell stimulation, indicating that the MAIT cells are incompletely identified by the expression of TRAV1-2 and CD161. MAIT cells in RA patients were constitutively more activated than conventional T cells suggesting prior ligand exposure. MAIT cells produced multiple cytokines after PMA and ionomycin stimulation. However, after stimulation with MR1 ligand 5-OPRU, MAIT cells from PB and synovial fluid produced predominantly TNF. In RA patients, disease activity score was negatively correlated with the proportion of PB MAIT cells and with 5-OPRU-stimulated TNF production.

Conclusion: MAIT cells account for a substantial proportion of CD4- T cells. RA PB and synovial MAIT cells produce TNF in response to 5-OPRU ligand derived from microbial riboflavin synthesis. Reduction of TNF-competent MAIT cells in PB of patients with high disease activity suggests migration to tissue inflammatory sites, where the TNF they secrete may drive RA pathology.

Disclosure: D. Jansen, None; E. Klinken, None; H. Nel, None; S. C. Law, None; H. Koppejan, None; M. Hameetman, None; L. Liu, None; A. Corbett, None; S. Eckle, None; D. Fairlie, None; R. E. M. Toes, None; F. van Gaalen, None; J. Rossjohn, None; J. McCluskey, None; R. Thomas, Janssen Pharmaceutica Product, L.P., 2,Janssen Pharmaceutica Product, L.P., 5.

To cite this abstract in AMA style:

Jansen D, Klinken E, Nel H, Law SC, Koppejan H, Hameetman M, Liu L, Corbett A, Eckle S, Fairlie D, Toes REM, van Gaalen F, Rossjohn J, McCluskey J, Thomas R. Mucosal-Associated Invariant T Cells Are an Important Source of TNF in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mucosal-associated-invariant-t-cells-are-an-important-source-of-tnf-in-rheumatoid-arthritis/. Accessed .

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