Session 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.
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 September 30, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mucosal-associated-invariant-t-cells-are-an-important-source-of-tnf-in-rheumatoid-arthritis/