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Tyrosine-protein phophatase non-receptor type 2 (PTPN2) deficiency increases short-lived effector T-cell survival and augments autonomous proliferation of T-cells

ABSTRACT: Whole proteome and phosphoproteome analysis of T-cells isolated from PTPN2 wild-type and knock-out micestrongly linked amplified T cell numbers to increased proliferation mediated by transcriptional activation of the signal transducer and activator of transcription (STAT) protein family. Subsequent analysis confirmed improved proliferation and survival but not an increase in initial engraftment to be the cause of higher T cell numbers upon adoptive transfer.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell

SUBMITTER: Jana Zecha

LAB HEAD: Bernhard Kuster

PROVIDER: PXD013122 | Pride | 2020-07-29

REPOSITORIES: Pride

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			Action	DRS
	MQSearchResult.7z	Other
	Phosphoprotome.7z	Other
	WholeProteome.7z	Other

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Publications

PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells.

Flosbach Markus M Oberle Susanne G SG Scherer Stefanie S Zecha Jana J von Hoesslin Madlaina M Wiede Florian F Chennupati Vijaykumar V Cullen Jolie G JG List Markus M Pauling Josch K JK Baumbach Jan J Kuster Bernhard B Tiganis Tony T Zehn Dietmar D

Cell reports 20200701 4

Manipulating molecules that impact T cell receptor (TCR) or cytokine signaling, such as the protein tyrosine phosphatase non-receptor type 2 (PTPN2), has significant potential for advancing T cell-based immunotherapies. Nonetheless, it remains unclear how PTPN2 impacts the activation, survival, and memory formation of T cells. We find that PTPN2 deficiency renders cells in vivo and in vitro less dependent on survival-promoting cytokines, such as interleukin (IL)-2 and IL-15. Remarkably, briefly ...[more]

PMID: 32726622

Similar Datasets

Differential gene expression in WT mice and mice lacking PTPN2 in T cells

Project description:WT mice and mice lacking PTPN2 in T cells (PTPN2-CD4Cre mice) were treated with AOM/DSS to induce colorectal tumours. RNA was isolated from tumour and non-tumour tissues in the colon. Colon samples from water-treated WT and PTPN2-CD4Cre mice served as additional control. Total RNA was isolated and the samples sequenced for polyA enriched RNA.

2020-10-03 | E-MTAB-9629 | biostudies-arrayexpress

Targeted transcriptome analysis of isolated intestinal epithelial cells from mice with constitutive Ptpn2-deficiency

Project description:Background & aims: Loss-of-function variants in the PTPN2 gene are associated with increased risk of inflammatory bowel disease. We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage communication, and modulation of the gut microbiome in mice, restricting expansion of a small intestinal pathobiont associated with inflammatory bowel disease. Here, we aimed to identify how Ptpn2 loss affects ileal IEC subtypes and their function in vivo. Methods: Constitutive Ptpn2 wild-type, heterozygous, and knockout (KO) mice, as well as mice with inducible deletion of Ptpn2 in IECs, were used in the study. Investigation was performed using imaging techniques, flow cytometry, enteroid culture, and analysis of gene and protein levels of IEC markers. Results: Partial transcriptome analysis showed that expression of Paneth cell-associated antimicrobial peptides Lyz1, Pla2g2a, and Defa6 was down-regulated markedly in Ptpn2-KO mice compared with wild-type and heterozygous. In parallel, Paneth cell numbers were reduced, their endoplasmic reticulum architecture was disrupted, and the endoplasmic reticulum stress protein, C/EBP-homologous protein (CHOP), was increased in Ptpn2-KO mice. Despite reduced Paneth cell number, flow cytometry showed increased expression of the Paneth cell-stimulatory cytokines interleukin 22 and interferon γ+ in CD4+ T cells isolated from Ptpn2-KO ileum. Key findings in constitutive Ptpn2-KO mice were confirmed in epithelium-specific Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2fl/fl control mice. Conclusions: Constitutive Ptpn2 deficiency affects Paneth cell viability and compromises Paneth cell-specific antimicrobial peptide production. The observed effects may contribute to the increased susceptibility to intestinal infection and dysbiosis in these mice.

2023-04-10 | GSE181923 | GEO

CRISPR screening reveals targets to reprogram long-lived effector CD8+ T cells for cancer therapy [microarray]

Project description:CD8+ T cells can be reprogrammed for better persistence and robust effector function in TME. By performing an in vivo pooled CRISPR-Cas9 mutagenesis screening of metabolism-associated factors, we identify Regnase-1 as a major negative regulator of antitumor responses, whose deficiency results in drastically increased CD8+ T cell accumulation in tumors We used microarrays to compare the global transcription profiles of Regnase1-null, Ptpn2/Regnase1-null and Socs1/Regnase1-null tumor infiltrating CD8+ T cell populations

2019-12-11 | GSE137016 | GEO

PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress

Project description:Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory environment, we generated a beta cell-specific deletion of Ptpn2 in mice (Ptpn2 βKO). While unstressed animals exhibit normal metabolic profiles, streptozotocin (STZ) Ptpn2 βKO mice display marked increase in hyperglycemia and death due to exacerbated beta cell loss. Furthermore, cytokine treated Ptpn2 KO islets resulted in mitochondrial defects and reduced glucose-induced metabolic flux, suggesting beta cells lacking Ptpn2 are more susceptible to inflammatory stress associated with T1D due to compromised metabolic fitness.

2023-12-01 | GSE215852 | GEO

Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [ATAC-seq]

Project description:Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors and loss of PTPN2 promotes T cell expansion and CD4 and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Treg) plays a role in autoimmunity. Here we show that a reduction in Ptpn2 expression, comparable to that reported in human carriers of autoimmune-predisposing PTPN2 variants, unexpectedly enhances the severity of autoimmune arthritis through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, Ptpn2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORgt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17 associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in RORgt+ Treg and that loss of function of PTPN2 in Treg contributes to the association between PTPN2 and autoimmunity.

2019-03-18 | GSE123486 | GEO

Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [RNA-seq]

2019-03-18 | GSE123484 | GEO

HiC-sequencing in human monocyte differentiation (3D-MO)

Project description:This dataset consists of in situ HiC-seq data from human monocytes, monocyte-derived dendritic cells as well as monocyte-derived cells that were subjected to siRNA treatment targeting CTCF or RAD21. In total, the data set includes 42 samples.

2022-06-24 | E-MTAB-10848 | biostudies-arrayexpress

Targeted transcriptome analysis of isolated intestinal epithelial cells from mice with constitutive Ptpn2-deficiency [ILEUM]

Project description:Loss-of-function variants in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene are associated with increased risk of inflammatory bowel disease (IBD). PTPN2 encodes T cell protein tyrosine phosphatase (TCPTP), a negative regulator of several intracellular signaling pathways including JAK-STAT. It has been shown that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC-macrophage communication, and modulation of the gut microbiome in mice. However, the mechanisms by which Ptpn2 influences the intestinal flora are unknown. In this study, we aimed to identify how Ptpn2-loss affects the expression of genes associated with function/differentiation of IECs in the small and large intestines that could contribute to higher susceptibility to infection.

2023-04-06 | GSE181914 | GEO

Targeted transcriptome analysis of isolated intestinal epithelial cells from mice with constitutive Ptpn2-deficiency [Proximal colon]

2023-08-02 | GSE181920 | GEO

Targeted transcriptome analysis of isolated intestinal epithelial cells from mice with constitutive Ptpn2-deficiency [Distal Colon]

2023-08-02 | GSE181916 | GEO