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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE49507 | GEO | 2014/03/02

SECONDARY ACCESSION(S): PRJNA214354

REPOSITORIES: GEO

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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:T cell antigen receptor (TCR)-mediated activation of T cells requires the interaction of dozens of proteins. Here we used quantitative mass spectrometry and activated primary CD4(+) T cells from mice in which a tag for affinity purification was knocked into several genes to determine the composition and dynamics of multiprotein complexes that formed around the kinase Zap70 and the adaptors Lat and SLP-76. Most of the 112 high-confidence time-resolved protein interactions we observed were previously unknown. The surface receptor CD6 was able to initiate its own signaling pathway by recruiting SLP-76 and the guanine nucleotide-exchange factor Vav1 regardless of the presence of Lat. Our findings provide a more complete model of TCR signaling in which CD6 constitutes a signaling hub that contributes to the diversification of TCR signaling.

| S-EPMC4037560 | biostudies-literature

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

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

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

A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function.

Project description:Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LATG135D) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LATG135D T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LATG135D T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LATG135D show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity.

| S-EPMC10063449 | biostudies-literature

Transcriptomic analysis of HCC1954 Parental(Pa), synchronous (S-BM), latent residual (Lat) or metachronous (M-BM) brain metastases cells

Project description:We did the transcriptomic profiling of HCC1954 Parental(Pa), synchronous (S-BM), latent residual (Lat) or metachronous (M-BM) brain metastases cells

2022-07-27 | GSE180098 | GEO

Methylation profile of latent metastatic (Lat-M) cells from clear cell renal cell carcinoma (ccRCC)

Project description:Lat-M cells were derived using ccRCC cell line 769-P (Parental, PA) cells to investigate determinants of metatatic latency in ccRCCs. We profiled methylation status of PA and LatM cells to understand epigenetic regulation of metastatic latency

2023-08-31 | GSE212176 | GEO

Gene expression profile of latent metastatic (Lat-M) cells from clear cell renal cell carcinoma (ccRCC)

Project description:Lat-M cells were derived using ccRCC cell line 769-P (Parental, PA) cells to investigate determinants of metatatic latency in ccRCCs. We profiled PA and LatM cells to understand gene expression in metastatic latency

2023-08-31 | GSE212175 | GEO

RNA-seq analysis of WT, CD5 KO, CD6 KO, CD5/CD6 double KO (I) and LAT KO naïve CD4+ T cells (II)

Project description:Transmembrane adaptors on T cells play crucial roles in TCR signal transduction. Although the TCR-LAT signal-transduction axis occupies a central place in T cell activation, it does not work in isolation and is tuned by other T-cell surface receptors among which stand the CD5 and CD6 receptors. Here we assessed the extent of transcriptional changes that initiated by TCR-CD28 pathways in the absence of CD5, of CD6, of both CD5 and CD6, or of LAT by RNA-seq analysis.

2020-09-29 | GSE148721 | GEO

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