Mouse infection models and studies in human infections have demonstrated that MAIT cells have a protective role. In a pulmonary infection model with the live vaccine strain Francisella tularensis, MAIT cells expand in the lung and produce the cytokines IFN-γ, TNF-α, and IL-17A, which are critical for controlling bacteria growth in an MR1-dependent manner. Importantly, MR1^−/− mice, which lack functional MAIT cells, have compromised bacterial clearance and delayed adaptive immune response in the lung but not in the spleen or liver (24). A similar increase in bacterial load has been observed in Klebsiella pneumoniae and Mycobacteria bovis BCG infection in MR1^−/− mice compared with that of wild-type mice (25, 26). An earlier study demonstrated the importance of MAIT cells in Mycobacteria tuberculosis infection in humans, and Mycobacteria abscessus and Escherichia coli infection using MAIT cell-specific TCR transgenic mice and in combination with MR1^−/− mice. Importantly, MAIT cells are depleted from peripheral blood and accumulate in the M. tuberculosis-infected lung of patients (21). Similar depletion of MAIT cells has been reported in individuals with active tuberculosis but not with latent infection, indicating that MAIT cells migrate to the infected lung only in the active disease (27). In addition, the remaining MAIT cells in the peripheral blood from active tuberculosis patients have compromised production of cytokines, such as IFN-γ and TNF-α, concomitant with higher expression of programmed death 1 (PD1), which indicates that M. tuberculosis infection not only depletes circulating MAIT cells but also undermines the effector function of MAIT cells (28). Furthermore, depletion of MAIT cells from peripheral blood is a risk factor in severely sick patients with sepsis for subsequent nosocomial infections and is correlated with the severity of cystic fibrosis, in particular, for those with chronic Pseudomonas aeruginosa infections (29, 30). These studies imply that MAIT cells somehow detect infection and migrate to the infection site where they may have a protective role. Given that the antigens for MAIT cells are compounds derived from bacteria-born vitamin B2 biosynthesis intermediates or adducts, it is not surprising that MAIT cells can detect bacterial infection in an MR1-dependent manner. However, MAIT cells can be activated by bacteria lacking the vitamin B2 biosynthesis pathway, such as in Enterococcus faecalis and Streptococcus pyogenes, probably in a TCR-independent manner (11). MR1-independent activation may be explained by stimulation of MAIT cells through innate pathways, such as IL-12 and IL-18, produced by monocytes or macrophages. This TCR-independent activation of MAIT cells and concomitant production of innate cytokines, IL-12 and IL-18, is important for protection against viral infections (see below).

Mucosal-associated invariant T cells are not activated by viruses, such as encephalomyocarditis virus, Sendai virus, Newcastle disease virus, herpes simplex virus, and parainfluenza 3 virus, even though these viruses can activate dendritic cells (21). However, many reports have shown that the frequency of MAIT cells is significantly decreased during human viral infections such as human immunodeficiency virus (HIV) infections (31–36) and HIV/M. tuberculosis co-infections (37). Furthermore, MAIT cell frequency poorly recovers in peripheral blood despite successful combined antiretroviral therapy (cART), whereas rectal and colon CD8⁺ MAIT cells are relatively well conserved (31, 32). By contrast, CD4⁺ MAIT cells are lost in rectal mucosa concomitant with depletion of CD4⁺ T cells in HIV patients (32). Although the exact mechanism of MAIT cell depletion from peripheral blood is poorly understood, depletion may be caused by activation-induced cell death (AICD) of MAIT cells (31) or exhaustion and downregulation of CD161 (35). While the latter possibility may be aided by MR1-tetramer, CD8⁺ MAIT cells tend not to be vulnerable to HIV infection (35). The reason for MAIT cell depletion during HIV infection remains elusive and warrants further study. Because T helper type 17 (Th17) cells are depleted in simian immunodeficiency virus-infected rhesus macaques with concomitant defects in mucosal barrier function (38), it is likely that HIV patients with MAIT cell depletion will have compromised immune response against bacteria or virus, and eventually succumb to opportunistic infection. Depletion of MAIT cells from circulation has also been observed in influenza virus-infected and hepatic C virus-infected patients (39, 40). Intriguingly, in both cases, MAIT cells exhibit an activated phenotype in patients, indicating that MAIT cells play a protective role in combatting virus infections. However, because MAIT cells do not recognize virus-born peptides and RNA/DNA, this phenotype probably reflects TCR-independent activation. Indeed, MAIT cells are activated by IL-18 in synergy with IL-12, IL-15, and IFN-α/β in virus infections (39). Thus, MAIT cells have a critical role in host protection against bacteria and virus infections and serve as a target for clinical intervention for development of vaccines and adjuvants that bolster host immunity.

Multiple sclerosis is an autoimmune disease characterized by inflammatory demyelination, gliosis, and axonal loss in the central nervous system (CNS) (41). Although autoreactive Th1 and Th17 have been suspected to cause diseases in the CNS, such as MS, neuromyelitis optica, and acute disseminated encephalomyelitis (42), the real pathogenic mechanism of MS is unknown. MAIT cells are depleted from peripheral blood in MS patients, particularly during relapse relative to remission (43, 44), but there is no difference in MAIT cell frequency between inactive and active MS patients (45) or even an increase during disease duration (46). FTY720 (fingolimod, a first-in-class drug for MS) therapy increases the relative frequency of MAIT cells (47). FTY720 is an antagonist of sphingosine-1-phosphate receptor and inhibits the egress of naive and central memory T and B cells from the lymph node. Importantly, FTY720 administration results in lymphopenia, in particular, in naive and central memory T and B cells harboring the chemokine receptor CCR7 (48). Because MAIT cells have an effector/memory phenotype, the increase of MAIT cells is not surprising, but the relative frequency of MAIT cells declines after prolonged treatment (47). Although CD8⁺ MAIT cells were found in postmortem brain lesion samples from MS patients, MAIT cells are depleted from peripheral blood concomitant with an increase in IL-18 in the serum, which suggests that MAIT cells migrate into the CNS lesion in MS patients (44). However, the role of MAIT cells in MS pathophysiology remains obscure. In contrast to human cases, the experimental autoimmune encephalomyelitis (EAE) murine MS model suggests that MAIT cells have a protective role in the pathogenesis of EAE because adoptive transfer of NK1.1⁺ cells (containing MAIT cells) prepared from transgenic mice with the MAIT cell-specific invariant TCR mitigates disease severity (49). In support of the above data, MR1^−/− mice that lack functional MAIT cells have more severe EAE, which again suggests a protective role for MAIT cells in EAE. Although the authors attributed this protective effect to the production of the anti-inflammatory cytokine IL-10 from B cells in an MR1-independent manner and contingent upon inducible T cell co-stimulator (ICOS)-B7-related protein interaction (49), these data should be interpreted with caution. Since NK1.1⁺ cells potentially contain not only authentic MAIT cells but also other cell types, determination of the precise role of MAIT cells in EAE requires a more elaborate mouse model, such as one in a TCR-Cα^−/− background, that assures the absence of other T cells for adoptive transfer.

Because MAIT cells are preferentially located in the gut lamina propria of humans and mice (50), and MAIT development is dependent on commensal flora in mice (5), it is reasonable to assume that MAIT cells are implicated in gastrointestinal diseases, particularly those involved in mucosal immunity. X-linked lymphoproliferative (XLP) syndrome was the first identified inherited immunodeficiency associated with NKT cell defects. XLP is characterized by high susceptibility to Epstein–Barr virus infection, hemophagocytic lymphohistiocytosis, and hypogammaglobulinemia (51). XLP-1 is characterized by the deficiency of the signaling lymphocyte activation molecule (SLAM)-associated protein, and XLP-2 is caused by mutation in the X-linked inhibitor of apoptosis (XIAP) gene, which causes a significant loss of NKT and MAIT cells due to enhanced apoptosis (51, 52). Intriguingly, one out of six XLP-2 patients develops severe colitis (51). Because XIAP deficiency is correlated with an elevated risk of mortality in patients with colitis and also with enhanced apoptosis in MAIT cells, it suggests that MAIT cells have a protective role in colitis. Recent studies have demonstrated accumulation of MAIT cells in a lesion compared with that in a normal region within the ileum from patients with Crohn’s disease and in colons from active patients relative to non-active patients with ulcerative colitis (53, 54). In both cases, the frequency of circulating MAIT cells was lower in patients compared with that of healthy controls. Circulating MAIT cells are activated in colitis as evidenced by enhanced expression of Ki67, natural killer (NK) G2D, and B and T cell attenuator (BTLA) concomitant with increased IL-17 and IL-22 production (53) or by enhanced expression of CD69, IL-17, and IL-18 in the serum (54). Similar to MS, ligands that MAIT cells recognize in IBDs remain to be clarified. Identification of these ligands may reveal the role of MAIT cells in these diseases and whether MAIT cells have protective or deleterious effects.

Mucosal-associated invariant T cells are also implicated in regulating immune response in allogeneic transplantation. MAIT cell number failed to recover after allogeneic hematopoietic cell transplantation in both myeloablative and non-myeloablative recipients. It appeared that inflammatory cytokines and gut microbacteria such as Blautiaspp. were required to promote MAIT cell reconstitution (55). MAIT cells also suppressed the proliferation of conventional T cells, indicating that MAIT cells could influence Graft-versus-host disease (GVHD) (55). On the contrary, a study on autologous hematopoietic stem cell transplantation has shown that MAIT cells were resistant to myeloablative conditioning. More than 30% patients have recovered MAIT cell number after transplantation by day 60. The more MAIT cells pretreatment patients possess, the less severe infectious complications (56). Thus, insight into the functions of MAIT cells in allogeneic transplantation would shed much light on the mechanisms of GVHD and open a novel horizon to suppress or to mitigate GVHD.

Historically, antibiotics have been the primary choice for the treatment of bacterial infections. However, the recent emergence of antibiotic-resistant bacteria poses a serious concern for global public health (85). Although much effort has been devoted to developing novel antibiotics, adjuvants that potentiate the immune system, antivirulent reagents that impair the establishment of bacterial infection, and biological therapies, such as monoclonal antibodies and agonists for innate immunity and the microbiome, more time and money is needed for these strategies to bear fruit. Because MAIT and reMAIT cells are protective in bacterial infections and MAIT cells exert cytolytic activity against bacterial-infected epithelial cells (86), reMAIT cells may be used to fight antibiotic-resistant bacterial infections and candidiasis where MAIT cell ligands are present. Given that patients who do not recover from severe sepsis tend to acquire nosocomial infections (29), supplementation of reMAIT cells into these patients may reinforce the immune system and mitigate the disease (Figure 2). The mechanism through which MAIT cells protect against infection consists of direct activation of MAIT cells via TCR followed by production of cytokines and chemokines that directly or indirectly exert antibacterial activity, activation via IL-12R and IL-18R in MAIT cells through the production of IL-12 and IL-18 from monocytes and macrophages, or some combination thereof (11, 26). TCR-dependent or TCR-independent activation of MAIT cells is important for recovering the loss of MAIT cells in HIV-infected subjects. Although the frequency and function of circulating MAIT cells is less in HIV-infected patients [reviewed in Ref. (87)], there is no decisive way to overcome these defects. Because reMAIT cells produce an array of cytokines and chemokines to fight bacterial infection and are competent to lyse epithelial cells infected with bacteria, cell therapy with reMAIT cells may further strengthen the efficacy of cART by suppressing opportunistic infection by M. tuberculosis or non-tuberculous mycobacteria such as Mycobacterium avium complex (MAC) (88). Even though cART results in a partial recovery of the cytokine production potential of MAIT cells upon E. coli stimulation, in particular IFN-γ and IL-17, TNF-α production remains perturbed (32). Furthermore, the number of circulating MAIT cells does not recover to that in healthy patients, even after successful cART, whereas rectal MAIT cells numbers seem to recover (34). A similar approach is possible to treat patients infected with MAC, for which no efficacious treatment has been available to date. Because the cause and underlying mechanism remain elusive, it is tempting to assume that reMAIT cell infusion reshapes an undermined immune system in HIV-infected (and mycobacteria-co-infected) patients in combination with cART.

Bacterial infection has a Janus-like feature—in most cases infection deteriorates health and threatens life, but in some select cases, intentional inoculation of bacteria, such as Streptococcus erysipelatis, a causative agent for the erysipelas, results in regression or complete disappearance of sarcoma (89). These seemingly contradictory results are important in that more detailed knowledge of bacterial infection and resultant immune reactions will aid understanding our immune system and open new avenues for cancer treatment (Figure 2). Although MAIT cells have been implicated in cancer, their precise role largely remains obscure. However, recent studies suggest that MAIT cells exert antiproliferative and even cytolytic activity against cancer cells in a cell–cell contact-dependent manner (67, 69). Because cytolytic activity of MAIT cells against bacteria-infected cells is dependent on MR1 (86), it is important to identify ligands that MAIT cells recognize through the cognate TCR in cancer. This not only will serve as a novel anticancer drug but also will expand a new horizon in MAIT cell biology—how MAIT cells distinguish normal cell from cancer cells. In particular, the underlying mechanism for BCG instillation, the standard therapy for bladder cancer and especially for non-muscle invasive bladder cancer, is still unknown (90) but may involve MAIT cells. Because MAIT cells are found in the urine of patients with urinary tract infection (UTI), and murine MAIT cells are recruited to the bladder upon bacterial infection and contribute to bacterial clearance in UTI model (91), it is plausible that BCG instillation somehow induces recruitment and activation of MAIT cells in bladder cancer, in particular at the mucosa or submucosa, and that leads to destruction of cancer cells (86, 91). Thus, studying MAIT cells in bladder cancer will provide not only mechanistic insight into the role of BCG but also be pertinent to the disease state and efficacy of BCG in patients, which could serve as a biomarker for diagnosis or prognosis. Irrespective of a patient’s infection state, whether reMAIT infusion confers anticancer activity and inhibits tumor growth awaits future study. It is worth noting that reMAIT cells would have to be considered for specific cancers in which MAIT cell ligands are available, such as colorectal cancer or in combination with microbe-based therapy as discussed earlier, because the cytolytic activity of MAIT cells would be dependent on microbial ligands presented on MR1. The use of reMAIT cells in cancer treatment is still its infancy and warrants further study.