The burgeoning role of MR1-restricted T-cells in infection, cancer and autoimmune disease

Crowther, Michael D.; Sewell, Andrew K.

doi:10.1016/j.coi.2020.12.002

Cited by 23 publications

(15 citation statements)

References 54 publications

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“…MR1 presentation can also occur to MR1-restricted T (MR1T) cells [42,43]. MR1 antigen presentation machinery involves vitamin B metabolites, namely derivatives of riboflavin and folate [43].…”

Section: Discussionmentioning

confidence: 99%

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Organ specific microenvironmental MR1 expression in cutaneous melanoma

Gordon,

So,

Azubuike

et al. 2023

Preprint

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The microenvironment is an important regulator of intertumoral trafficking and activity of immune cells. Understanding how the immune system can be tailored to maintain anti-tumor killing responses in metastatic disease remains an important goal. Thus, immune mediated eradication of metastasis requires the consideration of organ specific microenvironmental cues. Using a xenograft model of melanoma metastasis in adult zebrafish, we perturbed the dynamic balance between the infiltrating immune cells in the metastatic setting using a suite of different transgenic zebrafish. We employed intravital imaging coupled with metabolism imaging (FLIM) to visualize and map the organ specific metabolism with near simultaneity in multiple metastatic lesions. Of all the MHC complexes examined for brain and skeletal metastases, we determined that there is an organ specific expression ofmhc1uba(human ortholog,MR1) for both the melanoma cells and the resident and infiltrating immune cells. Specifically, immune clusters did not expressmhc1ubain brain metastatic lesions in immune competent fish. Finally, the differential immune response drove organ specific metabolism where tumor glycolysis was increased in brain metastases compared to skeletal and parental lines as measured using fluorescence lifetime imaging microscopy (FLIM). As MR1 belongs to the MHC class I molecules and is a target of immunotherapeutic drugs, we believe that our data presents an opportunity to understand the relationship between organ specific tumor metabolism and drug efficacy in the metastatic setting.

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Section: Discussionmentioning

confidence: 99%

“…None of the immune cells expressed MR1 in brain metastatic lesions in immune competent fish. MR1 has been implicated in riboflavin derived antigens from bacteria to Mucosal-associated Invariant T (MAIT) cells[42]. MR1 presentation can also occur to MR1-restricted T (MR1T) cells[42, 43].…”

Section: Discussionmentioning

confidence: 99%

Organ specific microenvironmental MR1 expression in cutaneous melanoma

Gordon,

So,

Azubuike

et al. 2023

Preprint

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“…These results showed that IL-12/IL-18 dominated the expression of cytotoxic factors, such as IFN-g and GrB, while the MR1/TCR-dependent pathway was related to IL-17 expression. Furthermore, activated MAIT cells express chemokine receptors CXCR3 and CXCR4 (involved in trafficking to the intestine) (15,(46)(47)(48), which may chemoattract MAIT cells from PB or non-pathological sites to the pathological site. This might be why in our study, the number of MAIT cells decreased in PB and increased in gut aGVHD lesion tissue at the onset of gut aGVHD.…”

Section: Discussionmentioning

confidence: 99%

The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Gao

Hong

Zhao

et al. 2021

Blood

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Background & Purpose: Gut acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high mortality. Mucosal-associated invariant T cells (MAITs) are a group of innate-like T cells enriched in the intestine that can be activated by riboflavin metabolites from various microorganisms. However, little is known about the function or mechanism of action of MAIT in the occurrence of gut aGVHD in the human body. Methods & Cases: In our study, multiparameter flow cytometry (FCM) was used to evaluate the number of MAIT cells (MAITs) and functional cytokines. 16S V34 region amplicon sequencing analysis was used to analyse the intestinal flora of transplant patients. In vitro stimulation and coculture assays were used to study the activation and function of MAITs. The number and distribution of MAITs in intestinal tissues were analysed by immunofluorescence technology. We prospectively studied the enrolled 150 consecutive patients who underwent allo-HSCT in our institute. Results: The number and frequency of MAITs in infused grafts in gut aGVHD patients were lower than those in non-gut aGVHD patients (Figure). Recipients with a high number of MAITs in infused grafts had a higher abundance of intestinal flora in the early post-transplantation period (+14 days). At the onset of gut aGVHD, the number of MAITs decreased in peripheral blood, and the activation marker CD69, chemokines CXCR3 and CXCR4 and transcription factors Rorγt and T-bet tended to increase. Furthermore, when gut aGVHD occurred, the proportion of MAIT17 was higher than that of MAIT1. The abundance of intestinal flora with non-riboflavin metabolic pathways tended to increase in gut aGVHD patients. MAITs secreted more granzyme B, TNF-α and IFN-γ under the stimulation of IL-12/IL-18 (non-TCR signal) and secreted most of the IL-17 under the stimulation of CD3/CD28 (TCR signal). MAITs inhibited the proliferation of CD4+ T cells in vitro. Conclusions: In conclusion, the lower number of MAITs in infused grafts was related to the higher incidence of gut aGVHD, and the number of MAITs in grafts may affect the composition of the intestinal flora of recipients early after transplantation. The flora of the riboflavin metabolism pathway activated MAITs and promoted the secretion of intestinal protective factors to affect the occurrence of gut aGVHD in humans. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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“…Major histocompatibility complex class 1-related gene protein (MR1) is a monomorphic antigen-presenting molecule ( Table 2 ). The default extracellular expression of MR1 is very low in the absence of its ligands and is upregulated under inflammatory condition activation ( 4 , 79 , 80 ). The primary role of MR1 is to present the conserved ligands of microbial metabolites to MAIT cells (most effective ligand 5-OP-RU and 5-OE-RU) ( 69 ).…”

Section: Mait Cells and Hematological Malignanciesmentioning

confidence: 99%

Mining the multifunction of mucosal-associated invariant T cells in hematological malignancies and transplantation immunity: A promising hexagon soldier in immunomodulatory

Gao

Zhao

2022

Front. Immunol.

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Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innate-like T cells capable of recognizing bacterial and fungal ligands derived from vitamin B biosynthesis. Under different stimulation conditions, MAIT cells can display different immune effector phenotypes, exerting immune regulation and anti-/protumor responses. Based on basic biological characteristics, including the enrichment of mucosal tissue, the secretion of mucosal repair protective factors (interleukin-17, etc.), and the activation of riboflavin metabolites by intestinal flora, MAIT cells may play an important role in the immune regulation effect of mucosal lesions or inflammation. At the same time, activated MAIT cells secrete granzyme B, perforin, interferon γ, and other toxic cytokines, which can mediate anti-tumor effects. In addition, since a variety of hematological malignancies express the targets of MAIT cell-specific effector molecules, MAIT cells are also a potentially attractive target for cell therapy or immunotherapy for hematological malignancies. In this review, we will provide an overview of MAIT research related to blood system diseases and discuss the possible immunomodulatory or anti-tumor roles that unique biological characteristics or effector phenotypes may play in hematological diseases.

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The burgeoning role of MR1-restricted T-cells in infection, cancer and autoimmune disease

Cited by 23 publications

References 54 publications

Organ specific microenvironmental MR1 expression in cutaneous melanoma

Organ specific microenvironmental MR1 expression in cutaneous melanoma

The Potential Roles of Mucosa-Associated Invariant T Cells in the Pathogenesis of Gut Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Mining the multifunction of mucosal-associated invariant T cells in hematological malignancies and transplantation immunity: A promising hexagon soldier in immunomodulatory

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