Cytokine Stimulation of PTPN2-deleted cancer cells
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE99299
PROVIDER: PRJNA388068 | ENA |
REPOSITORIES: ENA
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Project description:PTPN2 was deleted from a selection of murine and human cancer cells using CRISPR/Cas9. The loss-of-function phenotype was assessed in vitro with cytokine stimulation or vehicle control.
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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.
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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.
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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.
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Project description:An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways downstream of several cytokine pathways. All identified mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro cytokine reporter and phosphatase assays, and by hyperproliferation of patients’ T cells stimulated with cytokines. Furthermore, patients exhibited high serum levels of various inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in various STAT factors. Flow cytometry analysis of patients’ blood cells revealed typical alterations associated with autoimmunity, such as an expansion of CD11c+ B cells and follicular helper T cells, and all patients presented with anti-platelet or other autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.
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Project description:We used HDX-MS analysis to analyze the interaction between PTPN2 with a compound both in the presence and absence of the CRBN/DDB1 complex. We identified significant changes in HDX when PTPN2 was in the presence of compound. We also identified significant changes when comparing the deuteration profiles of PTPN2 in the presence of compound with and without the CRBN/DDB1 complex.
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Project description:Cellular and transcriptional experiments demonstrate that deletion of Ptpn2 enhances CD8+ T cell responses to chronic viral infection and cancer.
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