The MR1/MAIT cell axis reduces dystrophic neurite development in Alzheimer’s disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1140231 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29997563_1.fastq.gz | Fastqsanger.gz | |||
| SRR29997563_2.fastq.gz | Fastqsanger.gz | |||
| SRR29997564_1.fastq.gz | Fastqsanger.gz | |||
| SRR29997564_2.fastq.gz | Fastqsanger.gz |
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Project description:Plaques are a hallmark feature of Alzheimer’s disease (AD). We found that the loss of mucosal-associated invariant T (MAIT) cells and its antigen-presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting dystrophic neurites. Brain tissue from 5XFAD mice and those that are MR1-deficient (MR1 KO), were analyzed for dystrophic neurites, amyloid plaques, and synapses via immunofluorescence, RNA sequencing, ELISA, and Western blot. In 8-month-old 5XFAD/MR1 KO mice, there was reduced expression of LAMP1, Ubiquitin, and n-terminal APP in the hippocampus as compared to 5XFAD mice (p < 0.05). 5XFAD/MR1 KO mice also had less insoluble Aβ40 (p < 0.001) and higher levels of PSD95 (p < 0.01) in the hippocampus. Our data contribute additional mechanistic insight into the detrimental role of the MR1/MAIT cell axis in AD pathology development.
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Project description:Mucosal associated invariant T (MAIT) cells are lymphocytes that mediate tissue homeostasis and antimicrobial immunity. MAIT cells recognize microbial vitamin B-derived antigens (VitBAg) presented by MHC class I-related protein 1 (MR1). The cells that express MR1 and present VitBAg to MAIT cells remain unknown. We found that MR1 expression varies across tissues and cell types. Expression is regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacteria infection. Macrophages expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. We conclude that macrophages are key players in MR1 antigen presentation and MAIT cell immunity.
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Project description:Mucosal associated invariant T (MAIT) cells are lymphocytes that mediate tissue homeostasis and antimicrobial immunity. MAIT cells recognize microbial vitamin B-derived antigens (VitBAg) presented by MHC class I-related protein 1 (MR1). The cells that express MR1 and present VitBAg to MAIT cells remain unknown. We found that MR1 expression varies across tissues and cell types. Expression is regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacteria infection. Macrophages expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. We conclude that macrophages are key players in MR1 antigen presentation and MAIT cell immunity.
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Project description:MAIT cells (MAITs) represent an abundant T lymphocyte subset with unique specificity for microbial metabolites presented by the MHC-1b molecule, MR1. MAIT conservation along evolution indicates important, non-redundant functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed a transcriptomic analysis of murine MAITs in comparison with NKT subsets and with mainstream T cells in spleen and peripheral organs of B6-MAIT/CAST mice expressing a Rorc-GFP transgene. MAIT and NKT cells have been FACS-sorted after tetramer staining (MR1:5-OP-RU Tet+ for MAIT, CD1d:PBS57Tet+ for NKT), and 1/17 subsetting based on the expression of Rorc.
2018-12-03 | E-MTAB-7133 | biostudies-arrayexpress
Project description:IntroductionPlaques are a hallmark feature of Alzheimer's disease (AD). We found that the loss of mucosal-associated invariant T (MAIT) cells and their antigen-presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting dystrophic neurites.MethodsBrain tissue from 5XFAD mice and those that are MR1 deficient (MR1 KO), were analyzed for dystrophic neurites, amyloid plaques, and synapses via immunofluorescence, RNA sequencing, enzyme-linked immunosorbent assay, and western blot.ResultsIn 8-month-old 5XFAD/MR1 KO mice, there was reduced expression of lysosomal-associated membrane protein 1, ubiquitin, and n-terminal amyloid precursor protein in the hippocampus compared to 5XFAD mice (P < 0.05). 5XFAD/MR1 KO mice also had less insoluble amyloid beta 40 (P < 0.001) and higher levels of postsynaptic density protein 95 (P < 0.01) in the hippocampus.DiscussionOur data contribute additional mechanistic insight into the detrimental role of the MR1/MAIT cell axis in AD pathology development.Highlights5XFAD mice lacking the innate immune MR1/MAIT (mucosal-associated invariant T) cell axis (5XFAD/MR1 KO) have reduced numbers of dystrophic neurite markers in the hippocampus at 8 months of age. Hippocampal tissue transcriptional analyses showed reduced expression of genes encoding classical dystrophic neurite markers in 5XFAD/MR1 KO mice. 5XFAD/MR1 KO mice had less insoluble amyloid beta 40 and increased levels of the post-synaptic marker, postsynaptic density protein 95, in the hippocampus than did MR1+ 5XFAD mice.
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Project description:Mr1 knockout (Mr1−/−) mice, in which thymic cells lose the ability to promote the development of mature Mucosal-associated invariant T (MAIT) cells, induced systemic MAIT cell depletion. MAIT cells often exhibit altered functions during fibrosis and inflammatory diseases. Here we used intraperitoneal injections of 4.25% PD fluid (0.1 mL/g) daily for six weeks to mimic peritoneal dialysis (PD) related fibrosis in mice, and investigated whether Mr1 knockout could ameliorated PD-induced changes in peritoneal transcriptome. We analyzed bulk RNA-seq of peritoneums from Mr1+/+ + PBS group (n=3), Mr1+/+ + PD group (n=3), Mr1-/- + PBS group (n=2), and Mr1-/- + PD group (n=2), and demonstrated that Mr1 knockout could ameliorated PD-induced activation in fibrosis, hyperglycolysis, and mTORC1 signalings. In addition, the activation scores of these pathways are positively correlated with each other.
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Project description:MAIT cells are multifunctional innate-like effector cells recognizing bacterial-derived vitamin B metabolites presented by the non-polymorphic MHC class I related-1 molecule (MR1). Activated MAIT cells can exert regulatory, pro-inflammatory, or cytotoxic responses that enable the direct killing of infected cells. While tremendous progress regarding the multifaceted roles of MAIT cells has been made in the last decade, our understanding of the MR1-mediated responses of MAIT cells upon their interaction with other immune cells is still incomplete. Here, we performed the first translatome study of primary human MAIT cells interacting with THP-1 monocytes in a bicellular system. We analyzed the interaction between MAIT and THP-1 cells in the presence of the activating 5-OP-RU or the inhibitory Ac-6-FP MR1-ligand. Using bio-orthogonal non-canonical amino acid tagging (BONCAT) we were able to enrich selectively those proteins that were newly translated during MR1-dependent cellular interaction. Subsequently, newly translated proteins were measured cell-type-specifically by ultrasensitive proteomics to decipher the coinciding immune responses in both cell types. This strategy identified over 2,000 MAIT and 3,000 THP-1 active protein translations following MR-1 ligand stimulations. Translation of both cell types was more efficiently induced by 5-OP-RU in comparison to Ac-6-FP, which correlated with higher conjugation frequencies and CD3 polarization at immunological synapses. In addition to known effector responses, protein translations uncovered type I and type II Interferon-driven protein expression profiles in both 5-OP-RU-stimulated MAIT and THP-1 cells. Interestingly, the translatome of THP-1 macrophages suggested that activated MAIT cells can impact M1/M2 polarization in these cells. Indeed, gene and surface expression of CXCL10, IL-1, CD80, and CD206 confirmed an M1-like phenotype of macrophages being induced in the presence of 5-OP-RU-activated MAIT cells. Furthermore, we validated that the Interferon-driven translatome was accompanied by the induction of an antiviral phenotype in THP-1 cells, which were found able to suppress viral replication following conjugation with MR1-activated MAIT cells. In conclusion, BONCAT translatomics extended our knowledge of MAIT cell immune responses at the protein level and discovered that MR1-activated MAIT cells are sufficient to induce M1 polarization and an anti-viral program of macrophages.
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Project description:MAIT cells are multifunctional innate-like effector cells recognizing bacterial-derived vitamin B metabolites presented by the non-polymorphic MHC class I related-1 molecule (MR1). Activated MAIT cells can exert regulatory, pro-inflammatory, or cytotoxic responses that enable the direct killing of infected cells. While tremendous progress regarding the multifaceted roles of MAIT cells has been made in the last decade, our understanding of the MR1-mediated responses of MAIT cells upon their interaction with other immune cells is still incomplete. Here, we performed the first translatome study of primary human MAIT cells interacting with THP-1 monocytes in a bicellular system. We analyzed the interaction between MAIT and THP-1 cells in the presence of the activating 5-OP-RU or the inhibitory Ac-6-FP MR1-ligand. Using bio-orthogonal non-canonical amino acid tagging (BONCAT) we were able to enrich selectively those proteins that were newly translated during MR1-dependent cellular interaction. Subsequently, newly translated proteins were measured cell-type-specifically by ultrasensitive proteomics to decipher the coinciding immune responses in both cell types. This strategy identified over 2,000 MAIT and 3,000 THP-1 active protein translations following MR-1 ligand stimulations. Translation of both cell types was more efficiently induced by 5-OP-RU in comparison to Ac-6-FP, which correlated with higher conjugation frequencies and CD3 polarization at immunological synapses. In addition to known effector responses, protein translations uncovered type I and type II Interferon-driven protein expression profiles in both 5-OP-RU-stimulated MAIT and THP-1 cells. Interestingly, the translatome of THP-1 macrophages suggested that activated MAIT cells can impact M1/M2 polarization in these cells. Indeed, gene and surface expression of CXCL10, IL-1, CD80, and CD206 confirmed an M1-like phenotype of macrophages being induced in the presence of 5-OP-RU-activated MAIT cells. Furthermore, we validated that the Interferon-driven translatome was accompanied by the induction of an antiviral phenotype in THP-1 cells, which were found able to suppress viral replication following conjugation with MR1-activated MAIT cells. In conclusion, BONCAT translatomics extended our knowledge of MAIT cell immune responses at the protein level and discovered that MR1-activated MAIT cells are sufficient to induce M1 polarization and an anti-viral program of macrophages.
2023-02-08 | PXD039785 | Pride
Project description:MAIT cells are multifunctional innate-like effector cells recognizing bacterial-derived vitamin B metabolites presented by the non-polymorphic MHC class I related-1 molecule (MR1). Activated MAIT cells can exert regulatory, pro-inflammatory, or cytotoxic responses that enable the direct killing of infected cells. While tremendous progress regarding the multifaceted roles of MAIT cells has been made in the last decade, our understanding of the MR1-mediated responses of MAIT cells upon their interaction with other immune cells is still incomplete. Here, we performed the first translatome study of primary human MAIT cells interacting with THP-1 monocytes in a bicellular system. We analyzed the interaction between MAIT and THP-1 cells in the presence of the activating 5-OP-RU or the inhibitory Ac-6-FP MR1-ligand. Using bio-orthogonal non-canonical amino acid tagging (BONCAT) we were able to enrich selectively those proteins that were newly translated during MR1-dependent cellular interaction. Subsequently, newly translated proteins were measured cell-type-specifically by ultrasensitive proteomics to decipher the coinciding immune responses in both cell types. This strategy identified over 2,000 MAIT and 3,000 THP-1 active protein translations following MR-1 ligand stimulations. Translation of both cell types was more efficiently induced by 5-OP-RU in comparison to Ac-6-FP, which correlated with higher conjugation frequencies and CD3 polarization at immunological synapses. In addition to known effector responses, protein translations uncovered type I and type II Interferon-driven protein expression profiles in both 5-OP-RU-stimulated MAIT and THP-1 cells. Interestingly, the translatome of THP-1 macrophages suggested that activated MAIT cells can impact M1/M2 polarization in these cells. Indeed, gene and surface expression of CXCL10, IL-1, CD80, and CD206 confirmed an M1-like phenotype of macrophages being induced in the presence of 5-OP-RU-activated MAIT cells. Furthermore, we validated that the Interferon-driven translatome was accompanied by the induction of an antiviral phenotype in THP-1 cells, which were found able to suppress viral replication following conjugation with MR1-activated MAIT cells. In conclusion, BONCAT translatomics extended our knowledge of MAIT cell immune responses at the protein level and discovered that MR1-activated MAIT cells are sufficient to induce M1 polarization and an anti-viral program of macrophages.
2023-02-08 | PXD039804 | Pride
Project description:MAIT cells are multifunctional innate-like effector cells recognizing bacterial-derived vitamin B metabolites presented by the non-polymorphic MHC class I related-1 molecule (MR1). Activated MAIT cells can exert regulatory, pro-inflammatory, or cytotoxic responses that enable the direct killing of infected cells. While tremendous progress regarding the multifaceted roles of MAIT cells has been made in the last decade, our understanding of the MR1-mediated responses of MAIT cells upon their interaction with other immune cells is still incomplete. Here, we performed the first translatome study of primary human MAIT cells interacting with THP-1 monocytes in a bicellular system. We analyzed the interaction between MAIT and THP-1 cells in the presence of the activating 5-OP-RU or the inhibitory Ac-6-FP MR1-ligand. Using bio-orthogonal non-canonical amino acid tagging (BONCAT) we were able to enrich selectively those proteins that were newly translated during MR1-dependent cellular interaction. Subsequently, newly translated proteins were measured cell-type-specifically by ultrasensitive proteomics to decipher the coinciding immune responses in both cell types. This strategy identified over 2,000 MAIT and 3,000 THP-1 active protein translations following MR-1 ligand stimulations. Translation of both cell types was more efficiently induced by 5-OP-RU in comparison to Ac-6-FP, which correlated with higher conjugation frequencies and CD3 polarization at immunological synapses. In addition to known effector responses, protein translations uncovered type I and type II Interferon-driven protein expression profiles in both 5-OP-RU-stimulated MAIT and THP-1 cells. Interestingly, the translatome of THP-1 macrophages suggested that activated MAIT cells can impact M1/M2 polarization in these cells. Indeed, gene and surface expression of CXCL10, IL-1, CD80, and CD206 confirmed an M1-like phenotype of macrophages being induced in the presence of 5-OP-RU-activated MAIT cells. Furthermore, we validated that the Interferon-driven translatome was accompanied by the induction of an antiviral phenotype in THP-1 cells, which were found able to suppress viral replication following conjugation with MR1-activated MAIT cells. In conclusion, BONCAT translatomics extended our knowledge of MAIT cell immune responses at the protein level and discovered that MR1-activated MAIT cells are sufficient to induce M1 polarization and an anti-viral program of macrophages.
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