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Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE123488 | GEO | 2019/03/18

REPOSITORIES: GEO

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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

Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs

Project description:Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs

| PRJNA508897 | ENA

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

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

| PRJNA508900 | ENA

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

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

| PRJNA508898 | ENA

Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity.

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 (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, the presence of which results in a partial loss of PTPN2 expression, in mouse models of RA. We identified that reduced expression of Ptpn2 enhanced the severity of autoimmune arthritis in the T cell-dependent SKG mouse model and demonstrated that this phenotype was mediated 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 RORγt 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 mouse RORγt+ Tregs and that loss of function of PTPN2 in Tregs contributes to the association between PTPN2 and autoimmunity.

| S-EPMC6391091 | biostudies-literature

Foxp3 promotes macrophage phagocytosis in AIS

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-31 | GSE206946 | GEO

Eomes regulates mitochondrial function and promotes survival of pathogenic CD4+ T cells during chronic inflammation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-23 | GSE247863 | GEO

Foxp3+RORgt+ TCR Sequencing

Project description:TCR repertoire sequencing of mucosal Foxp3+RORgt+ regulatory T cells

| PRJEB15258 | ENA

IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms.

Project description:Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE-/- mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35-deficient (IL-35P35-deficient) mice on an ApoE-/- background and found Treg reduction in the spleen and aorta compared with ApoE-/- controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE-/- Tregs, and we have validated higher CCR5 expression in ApoE-/- Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE-/- have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.

| S-EPMC8525592 | biostudies-literature

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