Background/Purpose: Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes which are restricted by the MHC-related molecule-1 (MR1) and express a semi-invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. Previously, our group has reported that murine MAIT cells produced high levels of IL-17 and exacerbated arthritis by enhancing inflammatory responses by using animal models of arthritis. Recent studies have revealed that MAIT cells are abundant in humans. MAIT cells constitute about 5-10% of abT cells in peripheral blood and intestine, suggesting that MAIT cells may play important roles in human autoimmune diseases. In this study, we aimed to investigate whether MAIT cells are involved in the pathogenesis of rheumatoid arthritis (RA).

Methods: Peripheral blood mononuclear cells(PBMC) of RA patients and age- and sex- matched healthy subjects were separated by Lymphoprep. PBMC were stained with anti-human monoclonal antibodies against CD3, γδTCR, Vα7.2TCR, and CD161, and MAIT cells were identified as CD3⁺γδTCR^–Vα7.2TCR⁺CD161 ^high cells by FACS. The expression of HLA-DR and CCR9 on MAIT cells and other T cell subsets were also assessed. PBMC (2 x 10⁶ cells per well in 96-well culture plates) were stimulated with phorbol-myristate-acetate (50ng/ml) and ionomycin (500ng/ml) for 3 hours. Breferdin A was added in the last 2 hours of culture. After surface staining, cells were permeabilized by using BD Cytofix/Cytoperm Fixation/Permeabilization Solution Kit and intracellular cytokine staining for IL-17A, IFNγ, TNFα and IL-6 was performed. Cells were analyzed on FACS LSR Fortessa with Flowjo softwere.

Results: The percentages of MAIT cells were decreased in RA patients compared with healthy controls. The reduction in MAIT cell frequency was more enhanced in RA patients with active disease. There was a tendency of increased HLA-DR expression on MAIT cells from patients with lower MAIT cell frequencies. MAIT cells produced IL-17A , IFNγ, TNFα and IL-6 upon stimulation, and the frequency of IL-17A-producing MAIT cells was inversely correlated with that of MAIT cells in RA.  However, there was no correlation with the frequencies of IFNγ-, TNFα- or IL-6- producing cells and that of MAIT cells. We also found the negative correlations in the frequency of a gut-homing chemokine receptor CCR9-positive MAIT cells with that of MAIT cells in RA. 

Conclusion: We demonstrated that the frequency of MAIT cells was reduced in RA. The elevated expression of HLA-DR and IL-17 production by MAIT cells indicated the activated state of remaining MAIT cells in RA. The increase of CCR9-positive MAIT cells indicates the recruitment of gut MAIT cells to the peripheral blood in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/involvement-of-il-17-producing-mait-cells-in-the-pathogenesis-of-rheumatoid-arthritis/