Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Abstract

Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca2+/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide–stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Thus, CD56 bright NK cells are highly enriched and activated within synovial fluid from patients with psoriatic arthritis and rheumatoid arthritis (RA),122, 123 as well as in inflamed tissues in tuberculosis 124. Similarly, MAIT cells are also well established to be recruited to sites of inflammation,81, 125 and have been found to be enriched in the synovial fluid of patients with ankylosing spondylitis126 and RA127. They have also been shown to be recruited to the lung of patients with active tuberculosis infection,81, 82 increased in inflamed intestinal tissues in patients with inflammatory bowel disease,125 adipose tissues of obese patients,128 and are present in multiple sclerosis (MS) lesions 129, 130, 131.…”

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…Cho et al 19. report a reduced frequency of human MAIT cells in peripheral blood in patients with both SLE and rheumatoid arthritis (RhA), particularly in the CD8 + and double‐negative subsets, which correlated with disease activity scores in both conditions.…”

“…Moreover, most clinical data are only observational, making it hard to determine whether aberrations are primary phenomena, or perhaps represent a response to the effects of a disordered cytokine milieu 35. Indeed, given their remarkable abundance and the potential for TCR‐independent activation of MAIT cells by cytokines such as IL‐12, IL‐18 and IL‐23, the most important effects of MAIT cells in autoimmunity could be non‐specific amplification of inflammatory cytokines leading to increased IFN‐ γ 41 and IL‐17 19, 40. Differences between murine models and human studies may be due to such confounding factors in human studies as well as differences between the species.…”

“…without the need for prior clonal expansion14 – typically CD45RA − CD45RO + CD95 Hi CD62L Lo CD44 Hi 2, 15, 16, 17 – and can rapidly secrete a range of pro‐inflammatory cytokines including tissue necrosis factor‐ α (TNF‐ α ), interleukin‐17 (IL‐17) and interferon‐ γ (IFN‐ γ ), and also the type 2 cytokine IL‐4 on TCR ligation 15, 17. MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25.…”

“…MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25. A peculiarity of MAIT cell biology is that although MR1 expression is ubiquitous,3, 26 it is normally found only at very low levels on the cell surface 26, 27, 28.…”