Mucosal-associated invariant T (MAIT) cells belong to a family of innate-like T cells harboring semi-invariant T-cell receptors (TCRs) and recognize vitamin B2 metabolites as antigens on major histocompatibility complex class I-related gene protein (MR1) (Godfrey et al., 2019). MAIT cells play a pivotal role in immunity by bridging innate and adaptive immunities. They are abundant in humans, but rare in mice, and are associated with a number of diseases, such as bacterial and viral infections, autoimmune, inflammatory, and metabolic diseases, asthma, and cancer (Godfrey et al., 2015; Godfrey et al., 2019; Toubal et al., 2019). Although previous studies implicated MAIT cells in various tumors, their role in tumor immunity remains obscure. An analysis of infiltrating immune cells revealed that the high infiltration of CD8⁺CD161⁺ T cells, largely comprising MAIT cells, type 17 CD8⁺ T cells (Tc17 cells), and stem cell-like memory cells, in tumors represented a favorable prognostic signature across a wide array of human cancers (Gentles et al., 2015; Konduri et al., 2021). In mucosal-associated cancers, including lung and colon cancers, increases in MAIT cells in tumors were concomitant with a decrease in the circulation (Ling et al., 2016; Sundström et al., 2015; Won et al., 2016). While the high infiltration of MAIT cells in tumors negatively correlated with a favorable outcome in colorectal cancer (CRC) patients, the low infiltration of these cells in the tumors of hepatocellular carcinoma patients correlated with a poor prognosis, which is in contrast to the role of MAIT cells in tumor immunity (Zabijak et al., 2015; Zheng et al., 2017). Furthermore, the tumor microenvironment endowed by tumor-infiltrating lymphocytes, tumor-associated myeloid cells, and cancer-associated fibroblast plays a pivotal role in cancer progression and regression. Accordingly, tumor-residing MAIT cells exhibit an activated and/or exhausted phenotype as exemplified by the upregulation of CD39, PD-1, and CXCL13 upon the stimulation of TCR (Leng et al., 2019; Shaler et al., 2017; Yao et al., 2020). Consistent with these findings, tumor-infiltrating MAIT cells from CRC show the decreased production of cytokines that are pertinent to antitumor activity (Ling et al., 2016; Shaler et al., 2017; Sundström et al., 2015). Nevertheless, it currently remains unclear whether these changes positively or negatively affect the function of MAIT cells in tumor immunity (Cogswell et al., 2021). However, a recent study based on single-cell RNA sequencing revealed that approximately 50% of Tc17 cells in tumor-infiltrating T cells comprised MAIT cells across various tumors, and these Tc17 cells were particularly enriched in hepatocellular carcinoma and cholangiocarcinoma (Zheng et al., 2021). In addition, the frequency of Tc17 cells in melanoma patients correlated with responsiveness to anti-PD-1 therapy (Sade-Feldman et al., 2019; Zheng et al., 2021). The latter findings argue the antitumor activity of MAIT cells.

Based on these discrepancies, further studies are warranted to clarify the role of MAIT cells in tumor immunity in mice. However, difficulties are still associated with examining MAIT cells in mice for the following reasons. These cells are 10- to 100-fold less abundant in mice than in humans. Although the advent of MR1-tetramer (MR1-tet) has enabled the detection of murine MAIT cells, the paucity of these cells per se still hampers functional studies (Corbett et al., 2014; Rahimpour et al., 2015). Furthermore, there is a lack of appropriate mouse models to investigate the function of MAIT cells (Garner et al., 2018; Godfrey et al., 2019; Toubal et al., 2019). Although the development of MAIT cells is dependent on MR1, MR1-deficient mice do not necessarily reveal all aspects of MAIT cells because they are also devoid of other MR1-dependent cells and provide only limited information on immune cells that potentially interact with MAIT cells. Similarly, previous studies on MAIT cell-specific TCR transgenic mice revealed the protective roles of MAIT cells in bacterial infections, type I diabetes, and experimental autoimmune encephalitis (Chua et al., 2011; Croxford et al., 2006; Cui et al., 2015; Le Bourhis et al., 2010; Martin et al., 2009; Meierovics et al., 2013; Reantragoon et al., 2013; Sakala et al., 2015; Shalapour et al., 2012; Shimamura et al., 2011). However, the aberrant expression of transcription factors in MAIT cells impedes investigations on their precise roles in health and disease.

We herein used induced pluripotent stem cell (iPSC) technology to examine the role(s) of MAIT cells in immunity, particularly tumor immunity. We reprogrammed murine MAIT cells into iPSCs (referred to as MAIT-iPSCs), differentiated MAIT-iPSCs into MAIT-like cells (referred to as m-reMAIT cells), and adoptively transferred them into syngeneic immunocompetent mice to investigate their role. This approach not only allows us to assess the role of m-reMAIT cells as effector cells, it also provides insights into the interactions with other immune cells in tumor immunity.

In this study, we showed that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), an agonist of MAIT cells, and 5-OP-RU-loaded murine MR1-tet (mMR1-tet) both activated m-reMAIT cells, while these reagents induced the production of a similar, but not identical, set of cytokines and chemokines in the absence of antigen-presenting cells (APCs). When adoptively transferred, m-reMAIT cells migrated to different organs concomitant with the acquisition of maturation and prolonged mouse survival upon tumor inoculation. This tumor inhibitory activity was mediated through enhancements in the cytolytic activity of m-reMAIT cells by NK cells.

The present results imply that the adoptive transfer of m-reMAIT cells has potential as a novel tool for examining the immune functions of MAIT cells in health and disease.

The present results revealed that m-reMAIT cells were competent in TCR signaling. The activation of m-reMAIT cells and subsequent production of cytokines and chemokines in the absence of APCs suggested that 5-OP-RU directly operated via MR1 in m-reMAIT cells (Figure 1D–F). 5-OP-RU may be passively transported into cells, which in turn promotes the release of antigen-loaded MR1 from the endoplasmic reticulum (ER) onto the plasma membrane, thereby enabling signaling via TCR in m-reMAIT cells (referred to as a cis-acting signal) regardless of the apparent absence of MR1 on the cell surface (Figure 1B and D, Figure 1—figure supplement 1I; McWilliam et al., 2016). In contrast, mMR1-tet directly binds to TCR on m-reMAIT cells and elicits signals (referred to as trans-acting signals). Therefore, 5-OP-RU and mMR1-tet may have elicited similar signals through serine/threonine and/or tyrosine phosphorylation or dephosphorylation via TCR, which ultimately resulted in a different profile of cytokine and chemokine production (Figure 1F–H and J; Gaud et al., 2018; Nausch and Cerwenka, 2008). In this respect, the signaling pathway(s) responsible for the production of IL-2, IL-4, MIP1α CCL3 (MIP-1α), and CCL4 (MIP-1β) may be common between 5-OP-RU and mMR1-tet. In contrast, mMR1-tet may have activated the signaling pathways pertinent to the activation of Th17 as evidenced by the production of Th17 cytokines, such as IL-17F, IL-22, and IL-23, concomitant with inflammatory chemokines, including CCL5, CCL2, CXCL1, and CXCL6, in addition to TNF-α (Figure 1F). These results suggest that mMR1-tet signals, in part, through NF-κB, while 5-OP-RU does not (Liu et al., 2017).

While 5-OP-RU induced protein tyrosine phosphorylation, the identity of these proteins remains unclear, except for LAT (Figure 1G and H). Since LAT forms a hub that interacts with many signaling molecules, such as transmembrane receptors, phosphatases, kinases, guanine nucleotide exchange factors, GTP-activating proteins, ion channels, transporters, and ubiquitin ligases, further studies will provide insights into the proteins responsible for MAIT-TCR signaling and reveal the differences in signaling between conventional T cells and MAIT cells (Malissen et al., 2014).

It is important to note that the challenge with mMR1-tet induced the activation of m-reMAIT cells and production of cytokines and chemokines. This suggests that MAIT cells prepared from animals, including humans and mice, are unintentionally stimulated during experiments. Therefore, the interpretation of data requires caution (Figure 1E, F and J).

Although a previous study suggested that MAIT cells comprise MAIT1 and MAIT17 subsets characterized by the Th1 and Th17 transcriptomes, respectively, the present results revealed that m-reMAIT cells produced Th1, Th2, and Th17 cytokines (Salou et al., 2019). This may reflect a developmental stage at which m-reMAIT cells are en route to functional maturation and m-reMAIT cells generated in vitro represent the most immature stage. Therefore, it is tempting to postulate that the interaction between nascent MAIT cells and double-positive thymocytes favors the differentiation of naïve MAIT cells into MAIT1 and MAIT17 in vivo. The results on the adoptive transfer of m-reMAIT cells indicated that nascent MAIT cells egressed from the thymus migrate into any organs concomitant with the upregulation of CD44, a cell adhesion receptor, memory, and/or activation marker (Figure 2B; Benlagha et al., 2005). It is of interest that the expression of IL-7Rα in m-reMAIT cells became quasi-equivalent to that in endogenous cells in the intestines. Since IL-7 from intestinal epithelial cells plays a pivotal role in their homeostasis, the upregulation of IL-7Rα in m-reMAIT cells may mirror an intrinsic and primary role in this homeostasis and/or in the integrity of the intestinal epithelial barrier (Rouxel et al., 2017; Shalapour et al., 2012). Alternatively, it may reflect the role of MAIT cells in IL-17A and Th1 cytokine production, which is dependent on IL-7 (Tang et al., 2013). Taken together with the time-dependent upregulation of CD44, increases in IL-18Rα and CXCR6 across organs indicated that m-reMAIT cells matured in the host. Thus, naïve m-reMAIT cells, defined as mMR1-tet⁺TCRβ⁺ cells generated in vitro, may be promoted maturation in terms of transcriptional program upon adoptive transfer into the recipient mice, as evidenced by the acquisition of cytokine receptors, the effector molecules involved in cytotoxicity and tissue repairing, and those relevant to tissue residency (Figure 2—figure supplements 2–4). Moreover, the silencing of transcripts relevant to V-D-J recombination may ensure the continuum of the identity of m-reMAIT cells in the recipient (Figure 2—figure supplement 5). These results have important implications for future cell therapy with human iPSC-derived MAIT cells. Further studies are needed to clarify whether and how the adoptive transfer of naïve m-reMAIT cells affects epigenetic states, and whether this change leads to the generation of bona fide MAIT cells.

m-reMAIT cell dose-dependent mouse survival indicated their tumor inhibitory activity and function as effector cells in tumor surveillance (Figure 3B). However, since three consecutive injections of m-reMAIT cells failed to confer survival superiority, the niche for MAIT cells appeared to be saturated. Therefore, further studies are warranted to investigate whether a lymphopenia-inducing regimen, such as irradiation and/or cyclophosphamide, confers a difference in survival.

The failure of m-reMAIT cells to inhibit tumor growth in situ regardless of their mobilization to the skin indicated their poor infiltration into tumors rather than the loss of antitumor activity (Figure 3—figure supplement 1). Therefore, future research that focuses on whether an intratumor injection of m-reMAIT cells inhibits tumor growth is needed.

While the importance of NK cells in tumor surveillance is well known, that of MAIT cells remains elusive (Cogswell et al., 2021; Guillerey et al., 2016; Sharma et al., 2017). The present results showing the NK cell-dependent activation of m-reMAIT cells and the subsequent production of inflammatory cytokines and chemokines suggested that NK cells stimulated the tumor inhibitory effects of MAIT cells (Figure 4A and B). Moreover, the enhanced expression of transcripts relevant to the cytolytic function of m-reMAIT cells upon an interaction with NK cells in vitro indicated that m-reMAIT cells exhibited cytolytic activity in vivo (Figure 4C–G). The upregulation of Grzb, Fasl, and Tnfsf10 in m-reMAIT cells suggested that cytolytic activity comprised exocytosis- as well as caspase-mediated killing (Rossin et al., 2019; Trapani and Smyth, 2002). NK cell depletion compromised the survival of mice, which is consistent with the above findings, further highlighting the role of NK cells in boosting the tumor inhibitory activity of m-reMAIT cells in vivo. While NK cells recognize NKG2D ligands and/or the lack of MHC I on tumor cells, the molecular mechanisms by which m-reMAIT cells recognize and eliminate tumor cells warrant further study (Nausch and Cerwenka, 2008).

Contrary to our results, MAIT cells have been shown to induce the metastasis of melanoma B16F10 (Yan et al., 2020). Although the reason for this discrepancy currently remains unclear, differences in the dynamics of MR1 shuttling between ER and the plasma membrane upon a 5-OP-RU challenge or putative ligand(s) present in the tumor milieu (TM) may be a key feature. Since LLC did not strongly upregulate MR1 on the cell surface when stimulated (Figure 4A), 5-OP-RU may have bolstered B16F10 tumorigenicity through MR1. The MR1-elicited signal may suppress the function of NK cells for B16F10, whereas that from putative ligand(s) present in TM via MR1 did not, thereby enhancing or preserving NK cell functions. Further studies are needed to elucidate the underlying mechanisms, which will provide a novel avenue for tumor immunotherapy with iPSC-derived MAIT cells.

Although we showed that m-reMAIT cells exhibited cytolytic activity against LLC together with NK cells in vitro (Figure 4C and E–G), difficulties are associated with demonstrating that m-reMAIT cells isolated from mice exhibit similar lytic activity ex vivo. This is due to the low recovery of m-reMAIT cells and the compulsory use of mMR1-tet in cell preparations, which may interfere with cytolytic activity. Furthermore, it currently remains unclear whether these results are applicable to other cancer cells, such as B16F10, if the use of 5-OP-RU enhances or inhibits the cytolytic activity of m-reMAIT cells. Furthermore, since the transcriptome in m-reMAIT cells upon adoptive transfer still differed from that in endogenous cells, caution is needed when extrapolating the present results to MAIT cells in vivo.

In summary, the adoptive transfer model with m-reMAIT cells used in this study opens a new avenue for exploiting the function of MAIT cells and providing insights into their interaction(s) with immune cells in immunity.

Sequencing data have been deposited in DDBJ under accession number LC637403 to LC637407. RNA-seq data for naïve m-reMAIT cells (L7), spleen m-reMAIT cells, liver m-reMAIT cells, LPL m-reMAIT cells , endogenous MAIT cells in Ly5.1 spleen, endogenous MAIT cells in Ly5.1 liver, and endogenous MAIT cells in Ly5.1 LP were deposited under the accession DRA013350 (hwakao-0001_Submission).

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   2. Wakao H

   (2021) DNA Data Bank of Japan

   ID LC637403. Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity.

   http://getentry.ddbj.nig.ac.jp/getentry/na/LC637403
2. 1. Sugimoto C
   2. Wakao H

   (2021) DNA Data Bank of Japan

   ID LC637404. Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity.

   http://getentry.ddbj.nig.ac.jp/getentry/na/LC637404
3. 1. Sugimoto C
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   (2021) DNA Data Bank of Japan

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   http://getentry.ddbj.nig.ac.jp/getentry/na/LC637405
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   ID DRA013350. Reprogramming and redifferentiation of mucosal-associated invariant T cells reveal tumor inhibitory activity.

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Author details

1. Chie Sugimoto

   Host Defense Division, Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0488-2931

2. Yukie Murakami

   Host Defense Division, Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, Japan

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Eisuke Ishii

   Department of Dermatology, School of Medicine, Dokkyo Medical University, Mibu, Japan

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Hiroyoshi Fujita

   Host Defense Division, Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, Japan

   Contribution

   Data curation, Methodology, Project administration, Resources, Validation

   Competing interests

   No competing interests declared

5. Hiroshi Wakao

   Host Defense Division, Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, Japan

   Contribution

   Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Validation, Writing - original draft, Writing - review and editing

   For correspondence

   hwakao@dokkyomed.ac.jp

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7851-0711

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