Vα7.2-Jα33 (TRAV1-2-TRAJ33) rearrangement was found to be enriched in human double-negative (CD4^-CD8^-, DN) α/β T cells and the phylogenetically conserved T cell population was described to express an invariant TCR combined with a limited set of Vβ chains in 1990s (6, 7). In mice, these T cells express the orthologous Vα19-Jα33 (TRAV1-TRAJ33) (7). Since 2003, the new T cell subsets were named mucosal-associated invariant T (MAIT) cells because they are present in mucosal tissues (8). Human MAIT cell subsets are mostly CD8α⁺ (median 79.7%) or DN (median 14.3%) with a minor subset being CD4⁺ cells (median 1.3%) (9), whereas most murine MAIT cells are DN although CD4⁺ and CD8⁺ subsets are detected in lower proportions and with varied frequencies in a tissue-specific manner (10). A recent study has found that human DN and CD8⁺ MAIT cells are functionally distinct subsets, and it is speculated that apoptosis-prone DN MAIT cells may be derived from the main CD8⁺ MAIT cell population (11). MAIT cells recognize metabolites from the bacterial riboflavin (vitamin B2) pathway that are presented by the major histocompatibility complex class 1-related molecule (MR1) (12, 13). MR1 tetramers have been developed for the specific identification of MAIT cells (14). MAIT cells have high surface expression of natural killer (NK) receptors such as C-type lectin CD161, NKG2D and NKP30 (15). The expression of surface markers, including CD45RO, CD95hi, CD27, CD26hi, CD44hi, CD122 and CD62Llo, identify MAIT cells as effector and memory phenotypes (16, 17). MAIT cells also possess high levels of specific homing receptors, such as chemokine CC receptor (CCR)6, CCR5, CCR9, chemokine CXC receptor (CXCR)6 and CXCR3, which are involved in cell migration to peripheral tissues, particularly the liver, intestine and inflammatory tissues (10, 15). However, the expression levels of CXCR2 (CD182), CXCR7, and lymph node homing receptor CCR7 (CD197) are low (18). Moreover, the high surface expression of a series of cytokine receptors such as interleukin (IL)-7, IL-12, IL-18 and IL-23 receptors is of great importance to MAIT cell activation in the absence of TCR stimulation (10, 19). In humans, the T-Box transcription factor TBX21 (T-bet), retinoicacid-related orphan receptor (ROR)γt and promyelocytic leukemia zinc finger (PLZF) transcription factors are coexpressed, suggesting the type1, type 17, and innate-like functionality of MAIT cells (10, 16, 17) ( Figure 1 ).

MAIT cells are not only enriched in mucosal tissues, but are also abundant in the blood (0.1-9.2%), liver (20-40%) and peripheral lymphoid organs under physiological conditions (8, 9, 20, 21). However, MAIT cells are less frequent in laboratory strains of mice (C57BL/6 and BALB/c) at homeostasis. The proportion is approximately 0.6% of T cells in mouse livers (10). MAIT cells develop in a thymus-dependent manner, similar to humans and mice, and they can be divided into three stages (17). Stage 1 MAIT cells are present only in the thymus and are mostly either double positive (DP) or CD4⁺CD8^- thymocytes, and they lack CD161 and CD27 surface markers (CD24⁺CD44^- in mice) (17). A small subset of stage 1 MAIT cells express RORγt, which is attributed to vitamin B2 metabolite transferring into the thymus (22). Stage 2 MAIT cells are present at low frequency in the periphery and are mostly CD4⁺CD8^- cells that express CD161^-CD27⁺ (CD24^-CD44^- in mice) with a low expression of T-bet and RORγt (17). MiRNAs may participate in the transition from stage 1 to 2, because in the absence of miR-181a/b-1, thymic MAIT cells show low expressions of ROR γt and T -bet (23). The maturation from stage 2 to stage 3 and acquisition of effector function are PLZF dependent, and commensal bacteria along with IL-18 play an important role in the process (17). Stage 3 MAIT cells acquire functional potential and start to migrate to peripheral organs. At stage 3, MAIT cells expressing CD161⁺CD27^pos-low (CD24^-CD44⁺ in mice) exhibit interferon (IFN)-γ-producing T-bet⁺ (MAIT-1) sublineage or IL-17 A producing RORγt⁺ (MAIT-17) (24). IL-2/IL-15 receptor β chain, inducible costimulatory (ICOS), the transcription factor (TF) Bcl11b and miR-155 are involved in regulating MAIT1 and MAIT17 cells differentiation (25–27). Recently, MAIT2 cells that express PLZF have been defined using single-cell RNA sequencing analysis, which are considered as developmental intermediates of MAIT1 and MAIT17 cells (28). MAIT cells undergo further maturation and expansion after leaving the thymus, and microbes play an important role in regulating the number of MAIT cells in the periphery (29, 30).

MAIT cells can be activated by two pathways as follows: via TCR signalling (MR1 dependent) or cytokine signalling alone (MR1 independent). Riboflavin derivatives presented by MR1 of antigen presenting cells (APCs) activate MAIT cells, while the folic acid product is a competitive inhibitor (31). Because riboflavin synthesis is broadly conserved among bacteria and fungi, MAIT cells respond to a diverse array of microbes, including known commensals (32, 33). Following MR1-mediated activation, MAIT cells rapidly produce a wide range of cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF), IL-17 and IL-22. These cytokines, either directly (IFN-γ, TNF and IL-17) or indirectly through cell proliferation (IL-22), promote cytolysis of the infected cells, thereby leading to the control of various infections (15, 32, 34, 35). MAIT cells can also be activated by inflammatory cytokines alone, such as IL-7, IL-12, IL-18, IL-15 and IFN-α/β, in a TCR-independent manner (19, 36, 37). MAIT cells are activated with no known antigens, for instance, during viral infections or sterile auto-immunities. Cytokine-dependent activation of MAIT cells leads to secretion of IFN-γ, TNF and granzyme B, which exert cytotoxic functions (36, 37). Transcriptomic analysis of E. coli- and TCR-activated MAIT cells has shown distinct transcriptional reprogramming, including altered pathways, transcription factors and effector molecules, which has been validated by proteomics and metabolomics (38). In E. coli -activated MAIT cells, the TWIST1 transcription factor has been identified as a key driver, showing high connectivity to cytokine and chemokine expression (38).

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies to nuclear antigens. Blood MAIT cell frequency and absolute number are significantly lower in SLE patients than in healthy controls (HCs) (44). Absolute MAIT cell numbers are correlated with age, lymphocyte count, and SLE disease activity index, indicating that MAIT cell levels may reflect disease activity in SLE. The percentage of IFN-γ⁺ MAIT cells is lower in SLE patients than in HCs, and IL-17⁺ or IL-4⁺ MAIT cell levels are similar between SLE patients and HCs (44). IFN-γ production by MAIT cells has been found to be mainly regulated by the nuclear factor of activated T cell (NFAT1) transcription factor, which is intrinsically defective in SLE patients. Moreover, MAIT cell frequency is significantly correlated with NKT cell frequency in SLE patients. In particular, α-GalCer–stimulated NKT cells show poor activation of MAIT cells in SLE patients in vitro, suggesting that NKT cell dysfunction influences MAIT cell dysfunction (44). Another study has found that the reduced frequency of MAIT cells in peripheral blood is due to increased cell death, and the expression of activation marker CD69 is correlated with disease activity (45). In addition, monocytes from patients with SLE have an increased capacity to present MR1 antigens and activate MAIT cells. But the antigens that activate MAIT cells in SLE patients remain to be identified. Cytokine analysis has revealed that the plasma levels of IL-6, IL-18 and IFN-α positively correlate with the activated state of MAIT cells in SLE and that MAIT cells are activated by cytokines, including IL-18 and IFN-α, in the absence of exogenous antigens. In the kidneys of SLE patients with class III and IV lupus nephritis, MAIT cells constitute a large proportion of CD3⁺ cells (46). In FcγRIIb^-/- Yaa mice, an animal model of SLE, more MAIT cells are activated in the kidneys than in the spleen, and the proportions of IL-17- or IFN-γ-expressing MAIT cells are higher in the kidneys than in the spleen. Furthermore, in MR1^-/- lupus mice, MAIT cell deficiency results in reduced disease severity, as evidenced by decreased autoantibody production and lower glomerulonephritis scores, and these effects are accompanied by reduced germinal center responses as well as reduced T cell and innate T cell responses (46). Researchers have also demonstrated that MAIT cells contribute to autoantibody production by B cells in vitro dependent on the CD40L-CD40 and TCR pathways (46).

Rheumatoid arthritis (RA) is a systemic inflammatory disorder and is characterized by chronic, erosive synovitis of diarthrodial joints. Many studies have reported that the MAIT cell percentage is decreased in the peripheral blood of RA patients, and circulating absolute MAIT cell numbers can reflect disease activity in RA (44, 47, 48). The synovial fluid of patients with RA has a higher percentage of MAIT cells than peripheral blood (44, 47). In early, untreated RA patients, the distribution of MAIT cells shifts from CD8⁺ to CD4⁺ MAIT cells, and MAIT cells express lower levels of CD161. Furthermore, CD69 expression of MAIT cells is lower in RA patients compared to HCs, and MAIT cells are hyporesponsive as indicated by minimal upregulation of CD25 and CD69 in response to E. coli stimulation (48). Peripheral blood and synovial fluid MAIT cells of RA patients produce more IL-17A compared to osteoarthritis (OA) patients on stimulation (49). In a MAIT cell-deficient MR1^-/- mouse model of arthritis, the disease severity of collagen-induced arthritis (CIA) is ameliorated, indicating that MAIT cells play a pathogenic role in RA (50). In addition, MAIT cells augment arthritis mainly by enhancing inflammation in arthritis rather than by a type II collagen-specific response. In vitro, it is revealed that IL-1β induces the proliferation of MAIT cells, and IL-23 promotes the production of IL-17 by MAIT cells in the absence of TCR stimulation, indicating that cytokine-mediated MAIT cell activation contributes to the exacerbation of arthritis (50).

Psoriatic arthritis (PsA) is a chronic inflammatory spondyloarthritis that occurs in combination with psoriasis and has related extraarticular manifestations. The frequency of MAIT cells in peripheral blood is lower in PsA patients than in OA patients, whereas a higher MAIT cell frequency is found in paired synovial fluid, suggesting that MAIT cells are recruited to joints (49). Most MAIT cells in the synovial fluid of PsA patients are of CD8⁺ and the memory (CD45RO⁺) phenotype. Synovial fluid MAIT cells of PsA patients produce significantly more IL-17A than those of RA and OA patients. Moreover, the expression of IL-23R in circulating MAIT cells is higher in PsA and RA patients than in OA patients and IL-23R is functionally active, as evidenced by the profound mitotic effect in the presence of rIL-23 (49). These findings indicate that MAIT cells are likely to be part of the IL-23/IL-17 cytokine network in the pathogenesis of PsA.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterized by abnormal ossification and ankylosis affecting the spine and sacroiliac joints. Peripheral blood MAIT cell frequency and number are reduced in AS patients compared with HCs; however, MAIT cell frequency does not correlate with disease activity (47, 51, 52). The results obtained by Gracey et al. show that the level of CD69 of blood MAIT cells in AS patients is equivalent to that in HCs, while Hayashi et al. have found that CD69 expression on circulating MAIT cells correlates with the Ankylosing Spondylitis Disease Activity Score in patients with AS (47, 51). The discrepancy may be due to some factors, such as different disease stages and different treatments. MAIT cells are enriched in synovial fluid with high expression of CCR6. There is a higher percentage of IL-17⁺ and IL-22⁺ MAIT cells and a lower percentage IFN-γ⁺ MAIT cells in the blood of AS patients; in the paired synovial fluid of AS patients, TNF⁺ and IFN-γ⁺ MAIT cells are decreased, and the granzyme B⁺ and IL-17⁺ MAIT cell frequencies are increased (47, 52). Furthermore, IL-17 elevation in circulating MAIT cells of AS patients depends on priming with IL-7 but not IL-23 or MR1-presenting antigens (47).

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands leading to glandular dysfunction. pSS patients have a reduced frequency of MAIT cells, and MAIT cells are unable to be identified as a distinct population by CD161 and TCRVα7.2 in half of pSS patients (53). The blood MAIT cells in pSS patients are enriched in the naïve (CD45RA⁺, CCR7⁺) population and show an increase in CD4⁺ subset as well as a decrease in CD8⁺ subset. Compared to MAIT cells in HCs, circulating MAIT cells in pSS patients show lower activation status with lower CD154 and CD69 expression, and they produce less TNF and IFN-γ. There is no difference in the expression of IL-17, Th2 cytokines, granzyme A, granzyme B or perforin between MAIT cells from pSS and control subjects (53). MAIT cells are present in the salivary gland tissue of pSS patients but undetectable in control biopsies (53). However, another study has demonstrated that MAIT cells are IL-17 polarized in the salivary glands of patients with pSS, and that in vitro IL-7 and IL-23 stimulation of MAIT cells induces IL-17 over-expression only in pSS patients. In addition, different molecular pathways are explored: IL-7 stimulation induced STAT3/HIF1alpha up-regulation and IL-23 stimulation induced RORc over-expression (54).

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by immune dysregulation and progressive fibrosis that affects the skin and internal organs. The peripheral blood MAIT cell frequency is decreased in patients with SSc compared to HCs (55). However, the circulating MAIT cell frequency and absolute numbers do not correlate with C reactive protein (CRP), brain natriuretic protein, pulmonary involvement, median skin fibrosis scale, steroid amount or disease duration in patients with SSc.

Anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated (AAV) is an autoimmune disease characterized by inflammation and necrosis of blood vessel walls, which is accompanied by the presence of ANCA antibodies in serum. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The frequency of circulating MAIT cells is lower in patients with AAV compared to HCs, especially in MPA and GPA (56). MAIT cells in peripheral blood from AAV patients in the acute and remission phases exhibit an activated phenotype as judged by their increased expression of CD69 (57). The frequency of circulating MAIT cells that produce IFN-γ is increased in MPA and GPA patients, while the frequency of TNF and IL-17-producing MAIT cells is similar in AAV patients compared to controls (57).

Giant cell arteritis (GCA) is an immune-mediated vasculitis characterized by granulomatous inflammation that affects medium-sized and large arteries. MAIT cells are present in the arterial wall of GCA patients while the percentage of circulating MAIT cells is similar between untreated GCA patients and controls (58). The MAIT cells in GCA patients show decreased expression of CXCR3 and increased expression of IFN-γ. The percentage of circulating IFN-γ⁺ MAIT cells does not decrease after glucocorticoid therapy. MAIT cells from GCA patients proliferate and produce higher amounts of IFN-γ after treatment of IL-12 and IL-18, while the production of granzyme B and TNF is higher after activation of the TCR pathway. Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterized by pain and stiffness in the neck and pelvic girdle, which can occur independently or in association with giant cell arteritis. Among MAIT cells, the percentages of IFN-γ⁺ cells tend to be higher in PMR patients with active disease compared to patients with inactive disease, while the percentages of IL-17⁺ cells are comparable between the active and inactive patient groups. MAIT cells show greater activation in patients with PMR in remission than in controls and active patients as evidenced by a higher frequency of HLA-DR⁺CD38⁺ MAIT cells and CD69⁺ MAIT cells. Moreover, the frequency of HLA-DR⁺CD38⁺ MAIT cells is positively correlated with the PMR activity score and CRP level in patients in remission (59).

Dermatomyositis (DM) is an inflammatory disorder, characterized by classical cutaneous manifestations and inflammation of skeletal muscle. The frequency of MAIT cells is decreased in active DM patients in comparison with HCs, and the frequency increases after treatment (60). Reduced MAIT cell frequency is associated with increased expression of activation and exhaustion markers such as CD25, CD39 and CTLA4. There is no correlation between MAIT cell frequency and DM clinical scores or biological markers.