Altered composition and phenotype of mucosal-associated invariant T cells in early untreated rheumatoid arthritis

Abstract

BackgroundMucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise bacterial metabolites presented by MHC class I-related protein 1 (MR1). Bacterial dysbiosis has been implicated in auto-inflammatory disease development. We investigated MAIT cells in early, untreated rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients.MethodsBlood and synovial fluid mononuclear cells obtained from patients (SpA/RA) and controls were stimulated with fixed Escherichia coli to provide MAIT ligand. Cells were analysed by flow cytometry and MAIT cells were identified by MR1-5-OP-RU tetramers. Synovial biopsies were studied by confocal microscopy.ResultsPeripheral and synovial CD3+ MR1-tet+ MAIT cell frequencies were comparable in all groups. MAIT cells were detected in RA and SpA synovium based on CD3, CD161 and Vα7.2 expression. Peripheral RA MAIT cells were mostly CD4+ (controls 8.3%, SpA 12.3%, RA 52.6%; p < 0.001) and CD161 expression was strongly reduced (control mean fluorescence intensity (MFI) = 2348, SpA MFI = 2219, RA MFI = 226; p < 0.001). MAIT cells were hyporesponsive, shown by minimal upregulation of CD25 and CD69 to E. coli stimulation (control, CD25 MFI = 177, CD69 MFI = 1307; SpA, CD25 MFI = 95, CD69 MFI = 1257; RA, CD25 MFI = 0, CD69 MFI = 467; p < 0.001 and p = 0.01 respectively).ConclusionIn early untreated RA patients, the peripheral MAIT cell composition was altered, with reduced levels of CD161 expression, and cells were hyporesponsive to stimulation. MAIT cell dysfunction may provide a link between the microbiome and development of RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1799-1) contains supplementary material, which is available to authorized users.

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

“…Of note, these markers are validated to be associated with MAIT cells in the blood, but not as extensively in tissues, where some of them can be expressed by conventional T cells both at steady state and during disease. There are potential problems in using these surrogate markers to detect MAIT cells in settings other than healthy adult human blood. For example, there is growing evidence that the normal CD161 ++ phenotype of MAIT cells may be perturbed among donors (Figure ), under certain disease settings , and the proportion of CD161 ++ cells that are MAIT cells as defined by MR1 tetramer also alters with age . Furthermore, it is also worth considering that a reliance on TRAV1‐2 expression to detect MAIT cells will fail to detect those with atypical TCR α‐chain usages . It should be noted particularly for functional studies that the use of either TRAV1‐2 mAb or MR1‐tetramer poses the possibility of positive selection or activation of MAIT cells.…”

“…There are potential problems in using these surrogate markers to detect MAIT cells in settings other than healthy adult human blood. For example, there is growing evidence that the normal CD161 ++ phenotype of MAIT cells may be perturbed among donors (Figure ), under certain disease settings , and the proportion of CD161 ++ cells that are MAIT cells as defined by MR1 tetramer also alters with age . Furthermore, it is also worth considering that a reliance on TRAV1‐2 expression to detect MAIT cells will fail to detect those with atypical TCR α‐chain usages .…”

“…A major drawback to the use of this surrogate identification technique, however, is that is has been unclear as to whether all MAIT cells express high levels of the surrogate markers, and likewise, whether all TRAV1‐2 + cells that express high levels of the surrogate markers are MAIT cells, particularly in tissues. Indeed, clinical studies analyzing MAIT cells in HIV and rheumatoid arthritis have suggested that MAIT cells may downregulate CD161 during disease progression, raising concerns about the use of surrogate markers to identify MAIT cells in disease settings.…”

MAIT Cells Come to the Rescue in Cancer Immunotherapy?

“…Despite the broad heterogeneity of autoimmune and autoinflammatory diseases' etiology, several recurrent observations on phenotypical and functional alterations of MAIT cells were made. In the peripheral blood of patients diagnosed with different disorders {systemic lupus erythematosus [67], ankylosing spondylitis [68], rheumatoid arthritis (RA) [69], vasculitis [70], systemic sclerosis [71], primary Sjögren syndrome (pSS) [72], primary sclerosing cholangitis (PSC) [73] and inflammatory bowel disease [31,74], MAIT cells were shown to be significantly reduced. Of note, in some diseases, iNKT cell counts are also decreased, pointing towards a functional interdependence between the populations in these diseases.…”

Characterization of Human Mucosal‐associated Invariant T (MAIT) Cells

“…For example, the gene segment TRAV1‐2 is not exclusive to MAIT cells, with some MHC‐I‐restricted T cells (Tynan et al., , ) and CD1b‐restricted CD4 + germline‐encoded mycolyl lipid‐reactive (GEM) T cells also using this TRAV gene segment (Van Rhijn et al., ). CD161 expression by MAIT cells has been observed to be downregulated in diseases such as rheumatoid arthritis (Koppejan et al., ) and HIV (Freeman, Morris, & Lederman, ; Leeansyah et al., ). It appears to be reduced in response to stimulation; however, this may be caused by rapid division of activated MAIT cells that is seen in HIV‐infected patients and after bacterial stimulation in vitro (Freeman et al., ; Leeansyah et al., ).…”