MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands

Pavlovic, Marion; Gross, Christelle; Chili, Chahinaize; Sécher, Thomas; Treiner, Emmanuel

doi:10.3389/fimmu.2020.02097

Cited by 13 publications

(11 citation statements)

References 79 publications

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“…Viruses are devoid of the riboflavin synthesis machinery and consequently unable to activate MAIT cells in an MR1/ i TCR-dependent manner. However, many viral infections lead to MAIT cell activation, primarily driven by inflammatory cytokines such as interleukin (IL)-7, -12, -15, -18 and type I interferons (IFNs) 10–13 . The importance of MAIT cells in antiviral immune surveillance is evidenced by the heightened morbidity and mortality of influenza A virus (IAV)- infected Mr1 -/- mice that lack MAIT cells 14 .…”

Section: Introductionmentioning

confidence: 99%

Targeting the MR1-MAIT Cell Axis Improves Vaccine Efficacy and Affords Protection against Viral Pathogens

Rashu

Ninkov

Wardell

et al. 2023

Preprint

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Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. MAIT cells also sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unknown. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster mainstream virus-specific CD8+ T cell responses, and potentiate heterosubtypic antiviral protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency, Toll-like receptor 3 (TLR3) and cell-autonomous type I interferon receptor signaling. Furthermore, the observed phenomenon was manifest in young and old female and male mice, and could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.

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Section: Introductionmentioning

confidence: 99%

Targeting the MR1-MAIT Cell Axis Improves Vaccine Efficacy and Affords Protection against Viral Pathogens

Rashu

Ninkov

Wardell

et al. 2023

Preprint

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“…In humans, MAIT cells are found in several tissues and are preferentially located in blood and liver, where they represent 1-10% of T cells [12][13][14]. They not only recognise a limited number of ligands presented on the MHC-related 1 (MR1) protein, mainly derived from the bacteria riboflavin metabolite pathway, but also can be activated by cytokines [13,[15][16][17][18][19]. Activated MAIT cells produce numerous cytokines (including TNF-α, IFN-γ, IL-4, IL-17 and IL-22) and display cytotoxic activity [12,13,20,21].…”

Section: Introductionmentioning

confidence: 99%

MAIT cell alterations in adults with recent-onset and long-term type 1 diabetes

et al. 2021

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Aims/hypothesis Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αβ T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes. Methods MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2-14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes. Results MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25 + MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p < 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells, p < 0.01). Several MAIT cell variables correlated with HbA 1c level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (p < 0.05) and CD127 (IL-7R) (p < 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased. Conclusions/interpretation Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose home...

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“…The first reports analyzing MAIT cells functions in vitro showed these cells to be type 1/17 cytokines producers ( 25 ), as well as cytotoxic effectors against bacterially infected cells ( 70 ). Surprisingly, although MAIT cells are mostly effector/memory cells, their effector functions seemed to be difficult to engage, requiring co-stimulation by inflammatory cytokines such as IL-12, IL-15, IL18 or type 1 IFN, including in in vivo models ( 71 – 73 ). As MAIT-specific ligands like 5-OP-RU can be derived from non-pathogenic microbes, such as commensals, this was interpreted as the existence of a sail-safe mechanism to limit inappropriate MAIT cells activation in the absence of danger (inflammatory) signals.…”

Section: Problems To Overcome Questions To Addressmentioning

confidence: 99%

Mucosal-associated invariant T cells in hematological malignancies: Current knowledge, pending questions

Treiner

2023

Front. Immunol.

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Non-classical HLA restricted T cell subsets such as γδ T and NK-T cells are showing promises for immune-based therapy of hematological malignancies. Mucosal-Associated Invariant T cells (MAIT) belong to this family of innate-like T cell subsets and are the focus of many studies on infectious diseases, owing to their unusual recognition of bacterial/fungal metabolites. Their ability to produce type 1 cytokines (IFNγ, TNFα) as well as cytotoxic effector molecules endows them with potential anti-tumor functions. However, their contribution to tumor surveillance in solid cancers is unclear, and only few studies have specifically focused on MAIT cells in blood cancers. In this review, we wish to recapitulate our current knowledge on MAIT cells biology in hematological neoplasms, at diagnosis and/or during treatment, as well as tentative approaches to target them as therapeutic tools. We also wish to take this opportunity to briefly elaborate on what we think are important question to address in this field, as well as potential limitations to overcome in order to make MAIT cells the basis of future, novel therapies for hematological cancers.

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MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands

Cited by 13 publications

References 79 publications

Targeting the MR1-MAIT Cell Axis Improves Vaccine Efficacy and Affords Protection against Viral Pathogens

Targeting the MR1-MAIT Cell Axis Improves Vaccine Efficacy and Affords Protection against Viral Pathogens

MAIT cell alterations in adults with recent-onset and long-term type 1 diabetes

Mucosal-associated invariant T cells in hematological malignancies: Current knowledge, pending questions

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