The MR1/MAIT cell axis in CNS diseases

Abstract

Mucosal-associated invariant T (MAIT) cells are a subpopulation of innate-like T cells that can be found throughout the body, predominantly in mucosal sites, the lungs and in the peripheral blood. MAIT cells recognize microbial-derived vitamin B (e.g., riboflavin) metabolite antigens that are presented by the major histocompatibility complex class I-like protein, MR1, found on a variety of cell types in the periphery and the CNS. Since their original discovery, MAIT cells have been studied predominantly in their roles in diseases in the periphery; however, it was not until the early 2000s that these cells were first examined for their contributions to disorders of the CNS, with the bulk of the work being done within the past few years. Currently, the MR1/MAIT cell axis has been investigated in only a few neurological diseases including, multiple sclerosis and experimental autoimmune encephalomyelitis, brain cancer/tumors, ischemia, cerebral palsy, general aging and, most recently, Alzheimer’s disease. Each of these diseases demonstrates a role for this under-studied innate immune axis in its neuropathology. Together, they highlight the importance of studying the MR1/MAIT cell axis in CNS disorders. Here, we review the contributions of the MR1/MAIT cell axis in the progression or remission of these neurological diseases. This work has shed some light in terms of potentially exploiting the MR1/MAIT cell axis in novel therapeutic applications.

1. Introduction

Different subpopulations of innate-like T cells have been implicated in several diseases, be it infectious diseases, cancer or various autoimmune disorders. However, the depth of our understanding in terms of their contribution to these disorders is not quite to the extent that we know of for classical T cells when they are compared side-by-side functionally (Fig. 1). Two most commonly studied innate-like T cells are natural killer T (NKT) cells (Brutkiewicz et al., 2018) (which is not the focus of this review) and mucosal-associated invariant T (MAIT) cells (Treiner et al., 2003). Unlike the NKT cells that recognize lipid antigens presented by the major histocompatibility complex (MHC) class I-like CD1d molecule (Brutkiewicz, 2006; Brutkiewicz et al., 2018), MAIT cells recognize microbial-derived vitamin B-derived metabolites presented by the MHC class I-related molecule MR1 (Chiba et al., 2021; Corbett et al., 2020; Corbett et al., 2014; Harly et al., 2022; Klenerman et al., 2021; Salio, 2022). MR1 is expressed within and on a wide range of cell types (Abós et al., 2011; Hashimoto et al., 1995; Riegert et al., 1998; Uhlén et al., 2015; Uhlen et al., 2010). These include both hematopoietic and non-hematopoietic cells (Wang et al., 2019).

Fig. 1.

Four major pathways of antigen presentation for conventional and innate-like T cells. Classical major histocompatibility complex (MHC) class I and class II molecules present peptides to CD8+ and CD4+ T cells, respectively; MHC class I-like CD1d molecules present glyco- and phospholipids to nature killer T (NKT) cells; MHC class I-like MR1 molecules mostly present microbial vitamin B-derived metabolites to mucosal-associated invariant T (MAIT) cells.

MAIT cells have been shown to have functions in anti-microbial defense and anti-tumor responses (Crowther and Sewell, 2021; Karamooz et al., 2018; Keller et al., 2017a; Priya and Brutkiewicz, 2021; Treiner et al., 2003), be impacted both positively and negatively by virus infections (Hackstein and Klenerman, 2022; Long and Hinks, 2021; Samer et al., 2021) and facilitate wound healing (Constantinides et al., 2019; du Halgouet et al., 2023); however, they can also play a major role in the pathology of a variety of inflammatory disorders, such as inflammatory bowel disease (Giuffrida et al., 2018; Ju et al., 2020; Serriari et al., 2014; Tominaga et al., 2017).

The T cell receptor (TCR) of MAIT cells mainly consists of an invariant α chain with a Vα7.2/Jα33 rearrangement in humans (Vα19/Jα33 in mice), paired with a limited number of TCR β chains (Chiba et al., 2021; Harly et al., 2022; Klenerman et al., 2021; Salio, 2022). However, other human Jα chains (e.g., TRAJ12 and TRAJ20) can associate with Vα7.2 (Lepore et al., 2021; Reantragoon et al., 2013); these MAIT cells do nonetheless possess the critical Tyr95 residue within the CDR3α loop which is essential for MAIT cell activation (Reantragoon et al., 2012). Moreover, there can be modifications of the V-J germline junctions at the single nucleotide level (Treiner et al., 2003), which could be support for the argument that MAIT cells are not always strictly “invariant”.

Interestingly, MAIT cells are broken down into a variety of subpopulations: these are based upon whether MAIT cells consist of a CD8 αα homodimer or are CD8-negative (Brozova et al., 2016; Dias et al., 2018), their functional T cell activity (Vorkas et al., 2022) or their characterization based upon the transcriptional landscape that drives MAIT cell development and functional branching (Koay et al., 2019). This last report also identified the cytokine production bias for various MAIT cell subpopulations through each stage of differentiation (Koay et al., 2019). MAIT cells share several similar characteristics of another innate-like T cell subpopulation, NKT cells. For example, MAIT cells can directly kill cells via the expression of cytotoxic mediators, including perforin and granulysin (Kathamuthu et al., 2022; Rudak et al., 2018). Additionally, MAIT cells produce a variety of proinflammatory cytokines, including IFN-γ, TNF-α and IL-17A (Kawachi et al., 2006; Meierovics et al., 2013; Walker et al., 2012). Considering that they reside in the greatest numbers in the gut and lung, and are essentially absent in germ-free animals, it is believed that they also have an overall role in mucosal microbiome homeostasis (Constantinides, 2018). In conditions that involve dysbiosis, MAIT cells are reported to contribute to the observed pathology (Serriari et al., 2014).

As indicated above, the MR1/MAIT cell axis has been associated with several inflammatory disorders; this also includes the CNS. However, there are only a few CNS diseases where MAIT cells have been investigated. Interestingly, cancer was one of the first diseases in which MAIT cells were not only found, but also helped in their discovery within this disease context. Specifically, one of the first papers showed the presence of a subset of human T cells expressing the invariant Vα7.2-Jα33 MAIT cell TCR infiltrating tumors not only in the kidneys, but also the brain (Peterfalvi et al., 2008). This group made use of single-strand clonal polymorphism to determine the various subsets of T cells seen in biopsy tissues from both renal and brain tumors. Here, the clonal analysis revealed the presence of the MAIT cell invariant Vα7.2-Jα33 TCRα chain, along with Vβ2 and Vβ13 TCRβ chains (Peterfalvi et al., 2008). Now, the most common means by which one detects MAIT cells is via the use of fluorochrome-labeled MR1 tetramers loaded with the riboflavin intermediate, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) (Corbett et al., 2014; Reantragoon et al., 2013). This permits MAIT cell analysis by flow cytometry.

It is unknown how many MAIT cells are present in the human brain, although in mice we have found that MAIT cells comprise ~1% of the brain-resident mononuclear cells of wild-type mice (Priya and Brutkiewicz, 2020). Compared to humans, mice have significantly fewer MAIT cells in the body, with the liver containing less than 1%; in humans, this number ranges from 10–35% (Nel et al., 2021). This could mean that in the human brain there are more MAIT cells present. As such, it is important to understand how MAIT cells contribute to CNS disorders. This is particularly of interest, in light of a recent report showing that MAIT cells can preserve neuronal function in the meninges following reactive oxidative damage (Zhang et al., 2022).

This review will cover what is currently known about MAIT cells and MR1 in the few CNS disorders where they have been studied, whether they may be beneficial or detrimental in those cases, and if disease pathology mitigation targeting the MR1/MAIT cell axis might be a potential novel therapeutic strategy in at least some cases.

2. Glioblastoma and Other Brain Tumors

Glioblastoma multiforme (GBM) is a devastating and overly aggressive cancer of the brain (Qi et al., 2023; van Solinge et al., 2022). Current standard of care treatments for GBM include radiation, surgery, and chemotherapy with temozolomide (Rong et al., 2022). Despite years of research, the medical options remain limited. Unfortunately, the disease has a recurrence rate near 100% due to the aggressive nature of the tumor and its ability to evade the immune response (Kubica et al., 2021). This has led to a focus on the cell surface phenotypic identification of the infiltrating immune cells in the tumor microenvironment. In the earlier study mentioned above, the tumor-infiltrating MAIT cells that were found did not express the NK cell marker CD56 (Moretta et al., 1989); this is in contrast to MAIT cells isolated from the peripheral blood of patients with brain tumors (Peterfalvi et al., 2008). Moreover, most of the tumor-infiltrating MAIT cells expressed pro-inflammatory cytokines, although interestingly, mRNAs encoding IFN-γ or IL-17 were not detected. Considering their cytotoxic capacity (Le Bourhis et al., 2013), the authors suggested MAIT cells as a potential therapeutic option against brain cancers (Peterfalvi et al., 2008).

With regard to MR1 recognition by MAIT cells (Corbett et al., 2020), it is notable that, in the brain tumor samples studied above (Peterfalvi et al., 2008), along with the invariant α and β chains of the MAIT cell TCR, MR1 gene expression was also detected. This is suggestive that MAIT cells [or other MR1-restricted T cells, such as MR1T cells (Chancellor et al., 2022; Crowther and Sewell, 2021; Lepore et al., 2021)] can be activated by the presentation of tumor-derived antigens by MR1. Although the pro-inflammatory cytokines secreted by MAIT cells are thought to play a key role in the elimination of tumor cells, our recent studies have found a correlation between enhanced MR1 expression in glioma patient tumors and an overall poorer prognosis and reduced survival rate (Kubica et al., 2021). Glioma patients have a survival rate from 14 – 21 months following diagnosis (Bikfalvi et al., 2022). Although immunotherapy has had some successes in hematopoietic tumors (Nogami and Sasaki, 2022), it is substantially less effective against most solid tumors, even with the high MR1 expression that is detected in renal, breast and lung tumors (Kubica et al., 2021). To have a better understanding of how high MR1 expression contributes to the poor prognosis in glioma, we investigated the epigenetic regulation of MR1 (Kubica et al., 2021). An analysis of the DNA methylation patterns in the promoters within the MR1 gene in various tumors (including glioma) revealed that certain CpG sites within these promoter regions were hypomethylated; this likely led to the overexpression of MR1 (Kubica et al., 2021). Moreover, there is an upregulation of transcription factors such as IRF1, IRF2, CEPBP, and PRDM1, that bind to the MR1 promoter region and increase its expression in glioma (Kubica et al., 2021). Another important finding was the differential expression of MR1 across various grades of gliomas, with grade III having the highest MR1 expression and the poorest overall survival. Unlike the first stages of the disease, no MR1 DNA promoter region was hypomethylated in the terminal stage (i.e., grade IV). Thus, it is likely that there is an independent mechanism(s) governing increased MR1 expression and poorer survival outcomes. Further studies are needed to elucidate the possible mechanisms by which MR1 gene methylation patterns lead to MR1 overexpression in glioma cells and potential downstream effects on MR1-restricted T cells as possible immunotherapeutic targets.

In humans, MAIT cells are present at low numbers at birth. These then increase in the circulation and they migrate to different tissues in the body; the numbers then fall as a person ages (Le Bourhis et al., 2011). Considering that MAIT cells have the capacity to recognize and kill MR1⁺ cells presenting microbial antigens (Corbett et al., 2020), these cytotoxic properties of MAIT cells could be exploited in anti-tumor immunotherapy via adoptive transfer. Our laboratory has recently reported that artificial antigen presenting cells (aAPCs)—latex beads coated with 5-OP-RU (MAIT cell antigen)-loaded MR1 tetramers can selectively expand peripheral blood MAIT cells from normal humans. In culture, these MAIT cells were able to directly kill human GBM cell lines that presented MR1-bound microbial antigens (Priya and Brutkiewicz, 2021). Thus, expanding MAIT cells with aAPCs could potentially be quite useful in treating cancer patients with MR1-expressing tumors.

Whereas possible immunotherapeutic paradigms that could slow down the aggressiveness and the recurrence of gliomas have been tried, these tumors are still refractory to these approaches. The MR1-MAIT cell axis could be a key immunotherapeutic target, not only in the treatment of glioma, but also other solid tumors as well. This calls for further studies to investigate and identify tumor ligands presented by MR1 to MAIT/MR1T cells with the capacity to kill tumor cells in vivo.

3. Multiple Sclerosis

Multiple sclerosis (MS) is a CNS disorder in which the immune system attacks the myelin surrounding axons in the brain and spinal cord (Dobson and Giovannoni, 2019). There are four major courses of MS: 1. Clinically-isolated syndrome (CIS), the first episode of neurological symptoms and demyelination; 2. Relapsing-remitting MS (RRMS), which is characterized by clearly defined attacks between stages of remissions; 3. Secondary progressive MS (SPMS), which occurs after RRMS and at which time the patient no longer goes into a state of remission; 4. Primary progressive MS (PPMS), where there is continued or stalled progression of MS, but not remission. In MS, an increase in MR1 expression is correlated with a worse prognosis; this increase occurs specifically in brain regions with MS-associated lesions (Salou et al., 2016). Alongside elevations in MR1 expression, there are more MAIT cells in the cerebral spinal fluid, which decrease in abundance following treatment of MS neuroinflammatory symptoms (Carnero Contentti et al., 2019). This has also been shown in blood samples from MS patients in remission as compared to those in relapse. In remission, the frequency of MAIT cells is reduced (Miyazaki et al., 2011). Moreover, in PPMS patients in remission, there is a concomitant downregulation of mRNAs that encode RORγt, CCR6, CXCR6, and KLRK1/NKG2D, typical markers of MAIT cells (Acquaviva et al., 2019). That being said, it is important to point out that these markers can be expressed by other immune cell types (Dhar and Wu, 2018; Lee, 2018; Mabrouk et al., 2022; Meitei et al., 2021) and are not lineage-defining markers of MAIT cells.

In the peripheral blood of individuals with active MS, the abundance of IL-17⁺ MAIT cells is increased (Willing et al., 2018). However, in PPMS, the percentage of Tc17-like MAIT cells were found to be lower as compared to controls; this number was associated with a breakdown of myelin (Ammitzboll et al., 2020). MAIT cells are also reduced in number following treatment with alemtuzumab, a CD52-specific humanized mAb and dimethyl fumarate, which shifts the T cell cytokine production bias from proinflammatory Th1/Th17 to anti-inflammatory Th2 (Bomprezzi, 2015). In contrast, mAbs against the pan-B cell marker, CD20, such as ofatumumab, do not alter MAIT cell numbers in MS patients (Ammitzboll et al., 2020). Interestingly, all three drugs work differently on the immune system. Alemtuzumab binds to CD52, which in chronic lymphocytic leukemia depletes lymphocytes (Jordan et al., 2005). Whereas dimethyl fumarate is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator that decreases inflammation (Bomprezzi, 2015), the anti-CD20 mAb ofatumumab inhibits early-stage B cell activation (Zhang, 2009). Although it is generally unknown why only two of these drugs alter MAIT cell numbers, it is possible that the reduction in MAIT cells is not a direct effect of treatment; rather, the result of changes in the immune microenvironment. Thus, more studies are needed to fully understand how these therapeutic modalities impact the immune microenvironment in MS patients.

In contrast to those described above, other studies have found a reduction in circulating CD8⁺ MAIT cells from MS patients compared to healthy controls. In one case, within lesion areas of the brain, there were increases in CD8⁺Vα7.2⁺CD161^hi T cells with almost no MAIT cells in the CSF (Willing et al., 2014). Other studies showed there were no identifying changes in the CD26^hiCD161^hiCD8⁺ MAIT cell subpopulation between healthy individuals and adult MS patients (Ammitzbøll et al., 2017). This could be due to the stage of MS; it is also possible that age could play a role in the differences between MAIT cell subtypes. In adult PPMS patients over 35 years of age, there is a decrease in CD161^hiCD8⁺ circulating MAIT cells (Acquaviva et al., 2019). However, in children under 18 years of age, MAIT cells are increased in pediatric-onset MS (Mexhitaj et al., 2019). Typically, these CD161^hiCD8⁺ MAIT cells have been suggested to have a proinflammatory cytotoxic phenotype. However, in adult-onset MS, MAIT cells have been suggested to have a disease-suppressive role (Annibali et al., 2011; Illés et al., 2004; Miyazaki et al., 2011; Willing et al., 2014). Further studies are required to understand why MAIT cells may respond differently in pediatric- versus adult-onset MS. Together, these studies suggest that potential disease-dampening MAIT cells remain circulating in the blood, but the type of MAIT cells that are migrating into the brain remains to be determined and what effector functions are involved. This is important beyond just the number of MAIT cells and/or their cell surface phenotypes.

4. Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an induced CNS disease that is associated with infiltration of immune cells into the CNS which leads to inflammation. EAE is considered to be an animal model of MS (Dedoni et al., 2023). Like MS, EAE involves demyelination of the axons, defects in the processing of informational signals between nerve synapses and deteriorating paralysis developing throughout the body. To understand the mechanisms underlying the relationship between the MR1/MAIT cell axis in potentially alleviating symptoms of EAE, Croxford et al., used a transgenic mouse (Vα19iTg mice) expressing the Vα19-Jα33 MAIT cell TCR under the control of its natural promoter (Croxford et al., 2006). Here, EAE was induced by a classical method in which mice were injected with synthetic peptides derived from the myelin oligodendrocyte glycoprotein (MOG) suspended in Complete Freund’s Adjuvant and pertussis toxin. Interestingly, there was a suppression in the onset and development of EAE in these mice, along with a reduction in its severity. Thus, from these results, one could infer that Vα19-Jα33 TCR-expressing cells mediate an anti-inflammatory response in EAE. Moreover, histological studies revealed a decrease in the infiltration of monocytes into the CNS, along with diminished demyelination. This reduced monocyte infiltration was likely attributed to decreases in the expression of chemokine receptors and proinflammatory molecules that promote the trafficking of immune cells to the site of inflammation. Moreover, these transgenic T cells produced reduced levels of the proinflammatory cytokines IFN-γ, TNF-α, IL-2, and IL-17A, with a concomitant upregulation in IL-10 production, contributing to an anti-inflammatory response (Croxford et al., 2006).

Following the protective effects of Vα19iTg T cells in EAE above, the question was then asked whether a lack of MAIT cells could lead to exacerbation of EAE. Thus, MR1-deficient (MR1KO) mice were compared to wild-type non-transgenic and Vα19iTg mice. MR1KO mice lack MAIT (and all other MR1-restricted T) cells (Treiner et al., 2003). Notably, MR1KO mice displayed a severe form of EAE, had increased Th1 cytokine production and less IL-10 production. Thus, these data support the idea that MAIT cells have an immune-protective function in this model system in vivo. This was also confirmed in vitro with IL-10-secreting B cells (Croxford et al., 2006); this is especially relevant, as B cells are important antigen presenting cells for MAIT cells (Huang et al., 2008; Liu and Brutkiewicz, 2017). However, there is also the possibility of other types of immune cells coming into play, as IL-10 production is independent of MR1 expression (Croxford et al., 2006). Another aspect of an immune response is the presence of co-stimulatory molecules. The co-stimulatory molecule/ligand pairs of ICOS-B7RP-1, CD40-CD40L and CD28-CD80 are known to regulate cytokine secretion (Kitamura et al., 2000; Nishikawa et al., 2003). Inhibition of these co-stimulatory molecules with blocking antibodies confirmed the hypothesis that IL-10 production is regulated by these transgenic T cells through co-stimulatory signaling pathways.

Croxford et al., have proposed a novel experimental model system to study the clinical aspects of EAE along with possible therapeutic approaches that could prevent the onset and severity of EAE (Croxford et al., 2006). One complicating issue of this model, however, is the limitation of using a transgenic mouse only expressing the MAIT cell TCR α chain.

Overall and of concern, the mouse EAE studies suggesting a protective effect by MAIT cells seem to contradict those data from MS patients. One possible explanation is that in human MS, more MAIT cells produce IL-17A than in EAE in mice. Regardless, these differences suggest that some animal models that do not fully recapitulate all immune aspects of human disease and the difference in the immune response, need to be considered when using these models.

5. Neonatal encephalopathy/Cerebral Palsy

Neonatal encephalopathy (NE) is a complex and devastating disease seen in newborns with symptoms including alterations in their levels of consciousness, extreme seizures, poor reflexes, and an inability to breathe (Volpe, 2012). One of the most disturbing outcomes for neonates with NE is multiple organ failure (Hellmann et al., 2016). Neonatal encephalopathy further causes neurodevelopmental issues in the form of cerebral palsy, cognitive disabilities, and epilepsy (Korzeniewski et al., 2018; Kurinczuk et al., 2010).

It is known that most CNS disorders lead to inflammatory responses such as in hypoxia-ischemia or after an infection (Hagberg et al., 2002; Kölliker-Frers et al., 2021). This, in turn, causes the infiltration of various immune cells such as lymphocytes and macrophages, as well as cytokines and chemokines (Bajnok et al., 2017; Hagberg et al., 2015; Morkos et al., 2007; Taher et al., 2021; Zareen et al., 2020). These cellular subsets include natural killer (NK) cells, NKT cells, MAIT cells, and γδ T cell subsets. Taher et al., reported that whereas there is a significant increase in the frequencies and total number of T cells and B cells in patients suffering from NE and cerebral palsy, there was no evident difference in the absolute number and frequency of MAIT cells in NE (Taher et al., 2021). However, this study also found a decrease in MAIT cells in school-aged children with cerebral palsy as compared to age-matched children without this CNS disorder.

MAIT cells are present in low numbers in neonates (Ben Youssef et al., 2018), with a gradual increase seen as the child ages, reaching a plateau as an adult and then the numbers begin to decline in the elderly (Ben Youssef et al., 2018; Le Bourhis et al., 2011); we have observed this in mice as well (Wyatt-Johnson et al., unpublished). The reduced MAIT cell population in children suffering from cerebral palsy can likely be attributed to the different developmental stages of MAIT cells. It would be helpful here to assess the baseline expression of MR1 in B cells and dendritic cells present in the CNS microenvironment that could affect the activation and effector functions of MAIT cells.

6. Cerebral Ischemia

Cerebral ischemia occurs when blood flow is reduced or stopped as it travels into the brain (Zhao et al., 2022). It is well known that ischemic events attract the recruitment of immune cells to the site of injury; however, of these recruited immune cells, MAIT cells have only recently been studied. For example, one study demonstrated that MAIT cells are increased following ischemia compared to sham animals (Nakajima et al., 2021). In an MR1KO mouse model, the neurologic severity score was reduced 72 hours following cerebral ischemia. Interestingly, the infusion of an anti-MR1 mAb after cerebral ischemia also showed a reduced neurologic severity score, along with a reduction in the number of CNS cells that died following ischemia (Nakajima et al., 2021). These data suggest a detrimental role for MAIT cells in ischemia; however, whether the impact of an MR1 deficiency is due to the actual absence of MAIT cells in this model and not just a general reduction in the number of infiltrating cells overall has yet to be determined.

7. Aging and Alzheimer’s Disease

In normal aging, without any type of dementia, there are subtle reductions in cognitive functioning as well as altered immune function, known as immunosenescence (Aiello et al., 2019). In the C57BL/6 strain of mice, there is an increase in meningeal MAIT cells, with mice at 18-months having twice the number as those at 7-months of age (Zhang et al., 2022). ROS expression by MAIT cells in the meninges of 7-month-old mice is increased; this is thought to support meningeal barrier integrity, as there is a reduction in this integrity in MR1KO mice. Furthermore, 7-month-old MR1KO mice demonstrated reduced cognitive function in the Y-maze and Morris Water Maze. Interestingly, these behaviors were recovered when MAIT cells were adoptively transferred into MR1KO mice (Zhang et al., 2022). As a comparative analysis of cognitive function in 7-month vs. 18-month-old MR1KO mice was not performed in this study, this would be a good follow up experiment moving forward.

Unlike normal aging, Alzheimer’s disease (AD) is a type of dementia that causes a sharp decline in memory and cognitive functions. In AD, we found an increase in MAIT cell numbers in the 5XFAD mouse model of AD starting at 6-months of age in the hippocampus and in the cortex at 8-months (Wyatt-Johnson et al., 2023). Moreover, these MAIT cells displayed significantly increased expression of the classical T cell activation markers, CD69 and CD25; notably, there were no changes in these activation markers in conventional T cells. IBA1⁺ brain microglia/macrophages that were in close proximity to amyloid β plaques had increased levels of MR1 as compared to those further away or from wildtype C57BL/6 mice. Importantly, this latter finding in mice was also found in brain sections from AD patients vs. non-AD controls (Wyatt-Johnson et al., 2023). When 5XFAD mice were crossed onto an MR1KO background, there was reduced amyloid β pathology in the hippocampus until 8-months of age; in the cortex, significantly less amyloid β was present beyond 8-months of age (Wyatt-Johnson et al., 2023). Together, these data suggest a critical role for the MR1/MAIT cell axis in cognitive functioning during normal aging and a possible detrimental role during AD.

8. Discussion and Potential Future Therapeutic Options

More recently, there has been an increasing interest in the specific neuroimmune players in CNS diseases and injuries. Notably, very little work on innate immune axes in these conditions has been done. One immune axis that has been under the radar for some time involves the MHC class I-like MR1 molecule and an important innate-like T cell population that recognizes antigens presented by MR1, mucosal-associated invariant T (MAIT) cells—the subjects of this review.

We have only begun to scratch the surface in understanding the contributions of MR1, MAIT and/or other MR1-restricted T cells in the development or resolution of specific CNS diseases. Here, we have discussed those few CNS diseases in which the MR1/MAIT cell axis has been studied to at least some degree—from not even being the main focus of the work to investigations done in significant depth. Some studies have shown a positive and protective role in CNS disorders, whereas in others, elevations in MR1 expression and/or MAIT cell numbers are correlated with poor outcomes (Fig. 2). In those disorders in which MAIT cells are protective, their donor-unrestricted nature would allow broad access to MAIT cell-mediated immunotherapeutic approaches. In the case where MR1 and/or MAIT cells contribute to the disease, targeting MR1 might be an interesting therapeutic approach, focused on mitigating—or even preventing—the damage associated with MR1-dependent CNS disorders. An ideal model system to test this possibility could be Alzheimer’s disease (AD). In terms of therapeutic targeting of the MR1/MAIT cell axis in the context of AD, we do know that some drugs/drug-like compounds and even certain dietary molecules are able to bind to MR1—in some cases being able to inhibit MAIT cell activation (Keller et al., 2017b; Wang et al., 2022). Considering the variety of AD mouse models used by a number of laboratories throughout the world, this disease could be a good place to start.

Fig. 2.

Summary figure of the various CNS disorders discussed in this review. Some CNS disorders have MR1 and/or MAIT cell contributions that are reported to exacerbate or protect from the disease in the host. “MAIT cell-mediated killing of bacteria-infected tumors” comes from our report on human GBM (Priya and Brutkiewicz, 2021).

How might MR1-presented, microbial vitamin B-derived metabolites impact MAIT cell-dependent CNS diseases? We do know that the normal brain has resident MAIT cells. Could the introduction of microbes from the periphery (due to injury or BBB breakdown) result in phagocytosis of these microorganisms by microglia and subsequent presentation to MAIT cells via MR1? This could be possible in several CNS disorders. Do brain-resident MAIT cells then proliferate in response and/or do they enter the brain from the periphery to increase MAIT cell numbers in this organ? The answers to these questions have multiple ramifications in CNS diseases and could, potentially, lead to the identification of new and novel treatments.

Animal models can be extremely powerful tools in investigations of CNS diseases that impact patients. That being said, there are animal model systems out there that do not quite mimic the disease in patients. Certainly, mice are not humans, and the argument of “curing a mouse from cancer does not matter if the treatment does not work in patients” rings somewhat true here. Thus, we suggest that, as tractable as possible, newer animal models of some CNS disorders need to be developed. These should really parallel the disease/pathology seen in patients.

Overall, in the context of the contribution of the MR1/MAIT cell axis in CNS disorders, we would encourage the teaming up of neuroscientists with immunologists who study MR1 and the T cells that recognize them. Such collaborations will take investigations to the next level very rapidly, ultimately developing an in-depth understanding of the mechanisms of disease, and likely point to novel therapeutic targets that we have yet to discover—or even contemplate.

Highlights.

• The MR1/MAIT cell innate immune axis is understudied in CNS disorders

• Pathology in several CNS diseases involves MR1 and/or MAIT cells

• Elevated of MR1 expression in glioblastoma predicts a poor outcome for patients

• MAIT cell numbers are elevated in multiple sclerosis

• Not all animal models of immune-mediated CNS disorders truly reflect human disease