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Trib1 regulates T cell differentiation during chronic infection by restraining the effector program

ABSTRACT: Using the 10X Genomics platform, we performed single cell RNA-sequencing on activated T cells from LCMV clone 13-infected control or CD4-cre+ Trib1-floxed mice to determine how Trib1 regulates T cell population dynamics during chronic infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE143802 | GEO | 2020/03/05

REPOSITORIES: GEO

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Trib1 regulates T cell differentiation during chronic infection by restraining the effector program.

Project description:In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.

| S-EPMC7201917 | biostudies-literature

Trib1 regulates T cell differentiation during chronic infection by restraining the effector program

Project description:Trib1 regulates T cell differentiation during chronic infection by restraining the effector program

| PRJNA601744 | ENA

Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program.

Project description:Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein ? (C/EBP?) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBP?. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.

| S-EPMC6543518 | biostudies-literature

TRIB1 suppression on human hepatocytes transcriptome

2015-04-13 | GSE61473 | GEO

TRIB1 suppression on human hepatocytes transcriptome

Project description:The TRIB1 locus has been associated with lipid dysfunction. The underlying mechanisms were investigated by examining the transcription landscape in response to TRIB1 suppression in human primary hepatocytes. Primary hepatocytes from 3 distinct donors were exposed for 48 h to an antisense nucleotide targeting TRIB1 or a control nucleotide. The resulting impacts on the transcription profile were assessed using Human Transcriptome 2.0 microarrays (Affymetrix).

2015-04-13 | E-GEOD-61473 | biostudies-arrayexpress

The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state and its deletion improves checkpoint blockade

Project description:CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR+ TEX may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrated that deleting the pseudokinase Trib1 shifted TEX towards CX3CR1+ intermediates (TINT) with robust enrichment of KLR+ TEX (TKLR) via clonal T cell expansion. Adoptive transfer studies demonstrate this shift towards a CD8+ TKLR in Trib1 deficient cells is CD8-intrinsic, while CD4-depletion studies demonstrate that CD4+ T cells are required for optimal viral control in Trib1 conditional knockout mice. Further, Trib1 loss augmented anti-PD-L1 blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.

2023-07-25 | GSE235530 | GEO

Longitudinal single cell transcriptional and epigenetic mapping of effector, memory, and exhausted CD8 T cells reveals shared biological circuits across distinct cell fates [scRNA-Seq]

Project description:Longitudinal scRNA-seq from LCMV-specific P14 CD8 T cells in LCMV-Armstrong and LCMV-Clone 13 infection

2022-10-31 | GSE199563 | GEO

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [array]

Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBPa, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBPa by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML. We used microarrays to detail the global program of gene expression in mouse AML

2020-10-21 | GSE139641 | GEO

Longitudinal single cell transcriptional and epigenetic mapping of effector, memory, and exhausted CD8 T cells reveals shared biological circuits across distinct cell fates [scATAC-Seq 2]

Project description:Longitudinal scATAC-seq from LCMV-specific P14 CD8 T cells in LCMV-Armstrong and LCMV-Clone 13 infection

2022-10-31 | GSE199557 | GEO

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [ChIP-seq]

Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBP, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBP by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML.

2020-10-21 | GSE140313 | GEO

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