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Single-cell RNA-seq analysis of the lymphoproliferative disorders triggered by defective LAT signalosome. Modulation of the pathology in the context of two additional mutations, Stat6KO or Grap2KO

ABSTRACT: Single-cell RNA-seq analysis of the lymphoproliferative disorders triggered by defective LAT signalosome. Modulation of the pathology in the context of two additional mutations, Stat6KO or Grap2KO

PROVIDER: PRJNA865743 | ENA |

REPOSITORIES: ENA

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Single-cell RNA-seq analysis of the lymphoproliferative disorders triggered by defective LAT signalosome. Modulation of the pathology in the context of two additional mutations, Stat6KO or Grap2KO

Project description:LatY136F mice in which tyrosine 136 of the LAT adaptor is mutate accumulate CD4+ T cells that trigger a fast-onset autoimmune and inflammatory condition called LAT signaling pathology (LSP). Its histopathological manifestations resemble those of human IgG4-related disease (IgG4-RD), an inflammatory condition unifying a constellation of clinical entities leading to multi-organ damage. LatY136F mice deprived of STAT6 transcription factor develop a lymphoproliferative disorder with a kinetics and magnitude identical to that of LatY136F mice. Consistent with a role of STAT6 in Th2 differentiation, the LatY136F x Stat6KO lymphoproliferative disorder is characterize by a lymphoproliferation of both CD4 and CD8 Tc producing high levels of IFN-g. This Tc proliferation is associated with massive B cell proliferation and hyperglobulinemia G2a and G2b. Using single-cell RNA sequencing, we analyzed 48287 CD4 and CD8 T cells isolated from the spleen of LatY136F and LatY136F x Stat6KO mice over the period that leads to LSP installation. In this study, LatY136F lymphoproliferative disorder is also analyze in Grab2KO mice. Unexpectedly, LatY136F x Grap2KO mice present a lymphoproliferative disorder similar to the one observed in LatY136F mice but this time TCRgd Tc.

2022-11-30 | GSE210453 | GEO

Single-cell RNA-seq analysis of the T-cell lymphoproliferative and inflammatory disorders triggered by defective LAT signalosome

Project description:Single-cell RNA-seq analysis of the T-cell lymphoproliferative and inflammatory disorders triggered by defective LAT signalosome

| PRJNA787596 | ENA

Single-cell RNA-seq analysis of the T-cell lymphoproliferative and inflammatory disorders triggered by defective LAT signalosome

Project description:LatY136F mice in which tyrosine 136 of the LAT adaptor is mutated accumulate CD4+ T cells that trigger a fast-onset autoimmune and inflammatory condition called LAT signaling pathology (LSP). Its histopathological manifestations resemble those of human IgG4-related disease (IgG4-RD), an inflammatory condition unifying a constellation of clinical entities leading to multi-organ damage. Using single-cell RNA sequencing, we analyzed 5,030 CD4+ T cells isolated from the spleen of LatY136F mice over the period that leads to LSP installation. It charted the trajectory leading to full-fledged LSP and demonstrated that LSP involved T follicular helper (Tfh) cells, CD4+ cytotoxic T cells, and IgG1+ plasma cells. These cell types were also identified in the massive infiltrates found in LatY136F lung. Therefore, the LatY136F LSP entails all the cell types postulated to trigger human IgG4-RD. It offers the unique possibility to disentangle their pathological cross-talk as illustrated here using B cell-deficient LatY136F mice.

2022-11-30 | GSE190583 | GEO

Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub

Project description:The aim of the dataset was to study on a genome-wide level the impact of Lat deficiency on gene expression in resting and activated CD4+ T cells Lat+ and Lat? CD4+ T cells were isolated from lymph nodes and spleen of Latfl-dtr Tmat-Cre mice using a Dynabeads untouched mouse CD4 cells kit (Life Technology) and further purified by cell sorting. Lat+ CD4+ T cells were defined as: CD5+, hDTR+, CD8?, TCR???, CD25?, CD69?, CD62L+, lineage (CD11c, CD11b, CD19, CD45R, CD161)? and Lat? CD4+ Tcells were defined as: CD5+, hDTR?, CD8?, TCR???, CD25?, CD69?, CD62L+, lineage (CD11c, CD11b, CD19, CD45R, CD161)?. Sorted Lat+ or Lat? CD4+ T cells were then kept in vitro for 4 hours without stimulation or activated for 4 hours using anti-CD3 antibody and anti-CD28 antibody. Cell samples corresponding to three biological replicates were analyzed and gene expression profiles were obtained from total RNA.

2014-03-02 | E-GEOD-49507 | biostudies-arrayexpress

Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub

Project description:The aim of the dataset was to study on a genome-wide level the impact of Lat deficiency on gene expression in resting and activated CD4+ T cells

2014-03-02 | GSE49507 | GEO

Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT

Project description:T cell antigen receptor (TCR) signaling depends upon the kinases Lck and Zap70. Lck phosphorylates the TCR, facilitating Zap70 recruitment to the stimulated TCR. Lck also phosphorylates Zap70, relieving its auto-inhibition and activating its catalytic domain. Zap70 then phosphorylates the critical adaptors LAT and SLP76 which serve to nucleate key effector molecules required for downstream responses. However, mechanisms facilitating the interaction of Zap70 with its substrates have not been described. We report an evolutionarily conserved proline-rich motif in LAT is important for Zap70-induced phosphorylation of LAT and downstream signaling. This LAT proline-rich motif associated with the Lck SH3 domain, thereby facilitating Zap70-mediated phosphorylation of LAT and downstream functions. Our results suggest Lck orchestrates multiple steps in TCR signaling including the newly described facilitation of the interaction of Zap70 with its substrate LAT. This previously unrecognized feature of TCR proximal signaling may contribute to the development of more immunomodulatory therapies.

2019-11-12 | PXD008258 | Pride

Analysis of the interactome of LAT in CRISPR/CAS9 modified mouse CD+ T cells

Project description:Using a CRISPR/Cas9-based approach we engineer primary CD4+ T cells in which the LAT protein was tagged with an affinity Twin-Strep-tag (OST) with the purpose of determining by quantitative mass spectrometry the composition and dynamics of the signalosome assembling around LAT prior to and following T cell activation. Affinity purification of the OST tagged protein was performed using Streptactin beads, from T cells left non-stimulated, or stimulated for 30s or 120s with anti-CD3 and anti-CD4 antibodies. Each AP-MS purification is associated with a corresponding control (purification from non-edited WT CD4+ T cells, cultured and stimulated in the same conditions). The number of replicate biological experiments was n=3 for all conditions (time-points), and each sample was analyzed once by single-run nano LC-MS, resulting in 18 raw files.

2020-09-29 | PXD018526 | Pride

Drosophila COP9 Signalosome Subunit 7 interacts with multiple genomic loci

Project description:The COP9 signalosome protein complex has a central role in the regulation of development of multi-cellular organisms. While the function of this complex in ubiquitin-mediated protein degradation is well established, results over the past few years have hinted that the COP9 signalosome may function more broadly in the regulation of gene expression. Here, using DamID technology, we show that COP9 signalosome subunit 7 functionally associates with a large number of genomic loci in the Drosophila genome, and show that the expression of many genes within these loci is COP9 signalosome-dependent. This association is likely direct as we show CSN7 binds DNA in vitro. The genes targeted by CSN7 are preferentially enriched for transcriptionally active regions of the genome, and are involved in the regulation of distinct gene ontology groupings including imaginal disc development and cell-cycle control.

2014-09-22 | GSE61605 | GEO

Drosophila COP9 Signalosome Subunit 7 interacts with multiple genomic loci

2014-09-22 | E-GEOD-61605 | biostudies-arrayexpress

Additional succession

Project description:Additional samples in succession study

| PRJEB23628 | ENA