Intrahepatic microbes govern liver immunity by programming NKT cells
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ABSTRACT:
PROVIDER: PRJNA679769 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13091581.fastq.gz | Fastqsanger.gz | |||
| SRR13091582.fastq.gz | Fastqsanger.gz | |||
| SRR13091583.fastq.gz | Fastqsanger.gz | |||
| SRR13091584.fastq.gz | Fastqsanger.gz | |||
| SRR13091585.fastq.gz | Fastqsanger.gz |
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Project description:The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we show that the liver hosts a robust microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced the hepatic immune cell infiltrate by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promotes CCL5 signaling, which drives hepatic leukocyte expansion and maturation. Collectively, we reveal a microbial – glycosphingolipid – NKT – CCL5 axis that underlies hepatic immunity.
2022-05-17 | GSE161876 | GEO
Project description:The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.
| S-EPMC9012289 | biostudies-literature
Project description:Invariant Natural killer T (iNKT) cells are a separate lineage of T lymphocytes with innate effector functions. They express an invariant TCR specific for lipids presented by CD1d and their development and effector differentiation rely on a unique gene expression program. We asked whether this program includes microRNAs, small non-coding RNAs that regulate gene expression posttranscriptionally and play key role in the control of cellular differentiation programs. We identified a miRNA profile specific for iNKT cells, which exhibits features of activated/effector T lymphocytes. In this experiment we compared microRNAs of NKT cells versus those of conventional T lymphocytes, both extracted from wild type mouse thymus. To produce the populations we enriched mature thymocytes and then sorted NKT cells and conventional T cells (from one sorting we obtain one â??NKTâ?? sample and one â??Tâ?? sample). We performed the experiment in triplicate; the sample NKT 1 was sorted the same day of the sample T 1, NKT 2 with T 2, NKT 3 with T 3. We used a common reference approach for the 6 samples; as a common reference we produced RNA from total thymocytes, without the enrichment for mature cells and without the sorting; we pooled thymocytes derived from all the thymi used in the study. The aim of the experiment was to demonstrate that NKT cells have a microRNA profile different from that of conventional T cells.
2010-04-09 | E-GEOD-15925 | biostudies-arrayexpress
Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger) is encoded by the BTB domain-containing 16 (Zbtb16) gene. Its repressor function regulates specific transcriptional programs. During the development of invariant natural killer T (NKT) cells, PLZF is expressed and directs their effector program but the detailed mechanisms underlying PLZF regulation of multi-stage NKT cell developmental program are not well understood. This study investigated the role of acetylation-induced PLZF activation on NKT cell development by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZFON mice). NKT populations in PLZFON mice were reduced in proportion and numbers of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet+ NKT1 and RORt+ NKT17 subsets dramatically reduced, and the emergence of a T-bet-RORt- NKT cell subset with features of cells in early developmental stages rather than mature NKT2 cells. Preliminary analysis of DNA methylation patterns suggested that activated PLZF acts on the DNA methylation signature to regulate NKT cells’ entry into the early stages of development, while repressing maturation. In wild-type NKT cells, deacetylation of PLZF is possible, allowing subsequent NKT cell differentiation. Interestingly, development of other innate lymphoid and myeloid cells, that are dependent on PLZF for their generation, is not altered in PLZFON mice highlighting lineage specific regulation. Overall, we propose that specific epigenetic control of PLZF through acetylation levels is required to regulate normal NKT cell differentiation. Key points: Constitutive acetylation of PLZF (PLZFON) blocks NKT cell development. PLZFON might act on the DNA methylation signature to control gene expression. PLZF acetylation levels regulate normal NKT cell differentiation.
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Project description:Semi-invariant natural killer T (NKT) cells are thymus-derived innate lymphocytes that modulate microbial and tumour immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learnt regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-xL expression. Additionally, IL-15 regulated thymic developmental stage 2 (ST2) to ST3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic ST3 NKT cells. The loss of IL15-dependent T-bet expression resulted in poor expression of IFN-γ and several NK cell receptors in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-xL, and effector differentiation, which is regulated by T-bet. Gene expression was measured in NKT cells sorted from pooled thymi of wild-type (3 replicates) or IL-15 deficient (2 replicates) mice.
2011-12-08 | E-GEOD-32568 | biostudies-arrayexpress
Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger) is encoded by the BTB 42 domain-containing 16 (Zbtb16) gene. Its repressor function regulates specific transcriptional 43 programs. During the development of invariant natural killer T (NKT) cells, PLZF is 44 expressed and directs their effector program but the detailed mechanisms underlying PLZF 45 regulation of multi-stage NKT cell developmental program are not well understood. This 46 study investigated the role of acetylation-induced PLZF activation on NKT cell development 47 by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZFON mice). NKT populations in PLZFON 48 mice were reduced in proportion and numbers 49 of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet+ NKT1 and RORJt + 50 NKT17 subsets dramatically reduced, and the emergence of a T-bet - RORJt - 51 NKT cell subset 52 with features of cells in early developmental stages rather than mature NKT2 cells. Analysis 53 of DNA methylation patterns indicated that activated PLZF establishes a unique DNA 54 methylation signature to regulate NKT cells’ entry into the early stages of development, while 55 repressing maturation. In wild-type NKT cells, deacetylation of PLZF alleviates this 56 repression and allows subsequent NKT cell differentiation. Interestingly, development of 57 other innate lymphoid and myeloid cells, that are dependent on PLZF for their generation, is not altered in PLZFON 58 mice highlighting lineage specific regulation. Overall, we propose that 59 specific epigenetic control of PLZF through acetylation levels is required to regulate normal 60 NKT cell differentiation.
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Project description:We report the application of bulk RNA-sequencing-based technology for high-throughput profiling to examine the individual and combinatorial effects of the liver circadian clock and gut microbes on the liver transcriptome over 24-hours. Principle Component Analysis demonstrated that functionality of the liver circadian clock is the primary driver of the hepatic transcriptome profile, and presence of microbes is the secondary driver. We identified a range of significantly oscillating transcripts within each experimental group using empirical_JTK_CYCLE, and revealed an overall increase in oscillating transcripts with both the loss of cuntional liver clock and gut microbes. Network analysis via Spearman correlation revealed that a broken liver clock results in increased connections and correlated transcripts only in the presence of gut microbes. Finally, we show by differential expression and gene set enrichment analysis that several key metabolic pathways, particularly carbohydrate and lipid metabolism, were significantly downregulated when the liver clock is broken, regardless of microbial status. This study demonstrates the complex contributions of the liver circadian clock and gut microbes in transcriptome programming, both over time and overall.
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Project description:Analysis of DOCK8 deficient animals revealed a novel marker of NKT cell development, the integrin CD103. The role of CD103 was further investigated by RNA microarray comparing CD103 negative versus positive NKT cells. Total RNA was extracted from 3 biological replicates of thymic, CD103positive NKT cells and compared using an Illumina microarray to CD103negative NKT cells.
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