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MAP4K2 promotes Treg differentiation and suppresses antitumor immunity

ABSTRACT: MAP4K family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T-cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced FOXP3 gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was drastically improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adaptively transferred mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic patients showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of tumor immunity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Jurkat Cell

SUBMITTER: Huai-Chia Chuang

LAB HEAD: Tse-Hua Tan

PROVIDER: PXD070940 | Pride | 2025-12-16

REPOSITORIES: Pride

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			Action	DRS
	Mass_running_gel_20240822.pptx	Other
	Sample10_240906.mgf	Mgf
	Sample10_240906.raw	Raw
	Sample11_249006.mgf	Mgf
	Sample11_249006.raw	Raw

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Similar Datasets

MAP4K2 promotes Treg differentiation and suppresses antitumor immunity

Project description:MAP4K family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T- cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced FOXP3 gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was drastically improved in T-Map4k2 cKO mice, Treg-specific Map4k2- deficient mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic or lung cancer patients showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of tumor immunity.

2025-12-16 | PXD070831 | Pride

DUSP8 dephosphorylates Pur-alpha

Project description:Dual-specificity phosphatase 8 is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO) mice, mass spectrometry analysis, chromatin-immunoprecipitation sequencing, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, IL-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-DUSP8 cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of IL-9 mRNA levels in T cells and allergic responses of T-DUSP8 cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8–Pur-α interaction were indeed increased in the cytoplasm of T cells from human asthma patients and atopic dermatitis patients. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.

2023-09-30 | PXD044898 | Pride

Expression data from T-cells isolated from healthy mice or mice with polyposis

Project description:There is much controversy about the role of T-regulatory cells (Treg) in human colon cancer. High densities of tumor-infiltrating Treg can correlate with better or worse clinical outcomes depending on the sutdy. Treg have potent anti-inflammatory functions that have been shown to control cancer progression. However, Treg isolated from patient with colon cancer or in mouse models of polyposis do not have the ability to suppress inflammation and instead promote cancer. Gene expression was preformed to determine differences between Treg isolated from healthy mice and Treg isolated from polyp-ridden mice. Treg (CD4+Foxp3-GFP+) and CD4+ non-Treg (CD4+Foxp3-GFP-) were isolated from various organs of healthy Foxp3-GFP reporter mice or polyp-ridden Foxp3-GFPxAPCΔ468 reporter mice

2012-09-30 | E-GEOD-41229 | biostudies-arrayexpress

Mettl14-mediated m6A modification enhances the function of Foxp3+ regulatory T cells and promotes allograft acceptance

Project description:The transcripts levels of 434 genes were upregulated and those of 277 genes were downregulated in Treg cells from Foxp3-Mettl14f/+ cKO mice compared to those genes in Treg cells from the littermate controls.

2022-11-09 | GSE215371 | GEO

Single-cell RNA-seq on enriched cardiac fibroblasts from the healthy, sham or MI hearts of Hif-1a conditional knockout or heterozygous mice

Project description:In this project we explore the role of the master hypoxia regulator, Hypoxia inducible factor-1alpha (Hif-1a), in governing cardiac fibroblast (CF) function in homeostasis and following an acute ischaemic injury - myocardial infarction (MI). CF-specific Hif-1a conditional knockout (cKO) mice were generated by breeding Pdgfra-merCremer (PdgfraMCM/+) Cre recombinase driver mice with Hif-1a-floxed mice (Hif-1aflox/). In Hif-1afl/-; PdgfraMCM/+ progeny, Hif-1a could be conditionally deleted in adult CFs by tamoxifen (tam) administration. We also introduced a Cre-dependent R26tdTomato reporter allele allowing marking of Pdgfra+ CFs and their progeny. In this experiment, we first performed single-cell RNA sequencing (scRNA-seq) on tdTomato+ cells from the hearts of healthy cKO or heterozygous (HET) adult, male mice using the 10x Genomics Chromium system. We also performed scRNA-seq on tdTomato+/CD31-/CD45- cells from the hearts of cKO or HET mice at day-3 post-sham or -MI surgery.

2021-11-11 | E-MTAB-9583 | biostudies-arrayexpress

Comparison of gene expression in Wild type and T cell-specific conditional Trim28 KO in TCR stimulated and un-stimulated naive CD4 positive and T regulatory cells

Project description:A microarray study was performed in unstimulated and TCR-stimulated CD4 + T cells and Treg in wild type and conditional Trim28 KO mice to identify genes that are regulated by Trim28. These experiments constitute a portion of the study described below: Paper Abstract: Peripheral T cell activation and differentiation into specialized effectors are regulated by TCR- and cytokine-mediated signals that induce clonal expansion and unique transcriptional factors. These processes may include active chromatin modification by nuclear factors. In search of such molecules, we found Trim28, a component of large nuclear chromatin-regulatory complex is tightly controlled upon TCR stimulation at the level of phosphorylation, and examined global impact of Trim28 loss in especially CD4+ T cells, by generating T cell-specific conditional Trim28 KO mice (CKO). CD4+ T cells from CKO mice showed defective IL-2 production and T cell proliferation associated with defective upregulation of cell-cycle associated proteins. Accordingly, young CKO showed T-lymphopenia. Surprisingly, Trim28 CKO mice eventually accumulated auto-reactive memory-phenotype T cells that produced inflammatory IL-17. CKO mice are also susceptible to induced auto-inflammatory disease with TH-17 dominant immune response. Loss of Trim28 showed aberrant accumulation of TH-17 and FoxP3+ T cells, two key T cells in inflammation vs. tolerance. We found CKO T cells showed a cell-extrinsic promotion of TH-17 and FoxP3+ T cell development by a mechanism involving overproduction of TGF-beta. Our study revealed unexpected roles of Trim28, a global chromatin regulator in both T cell activation and tolerance. Trim28 conditional KO mice and age-matched control mice were sacrificed, and neive CD4+ T cells (CD4+CD62+CD25-) and Treg (CD4+CD62+CD25+) were sorted. Stimulation of naive T cells was done with anti-CD3 and anti-CD28 for 13 hours. We collected quadruplicates for each group.

2012-04-28 | E-GEOD-32224 | biostudies-arrayexpress

Tregs from Bcl11b-deficient versus wild type Tregs (CD4Cre and Foxp3Cre systems)

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A Stk4 -Foxp3-P65 Transcriptional Complex Promotes Treg Cell Activation and Homeostasis

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Gene expression profile at single cell level of tumor infiltrated Treg from the WT and the jmjd1c TregcKO mice

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