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Tumor rejection in Cblb-/- mice depends on IL-9 and Th9 cells

ABSTRACT: Casitas B lymphoma-b (Cbl-b) is a central negative regulator of cytotoxic T and NK cells, explaining its intracellular checkpoint function in cancer. Increasing evidence highlights the importance of CD4+ T helper cell populations (e.g., IL-9 producing T cells: Th9 cells) for anti-cancer immunity. We here provide experimental evidence that Cbl-b acts as rheostat favoring regulatory T cells (Treg) at the expense of Th9 cell differentiation. Adoptively transferred tumor-model antigen specific Cblb-/- Th9 cells exert superior anti-tumor activity leading to improved melanoma control in vivo. Accordingly, blocking IL-9 in melanoma cell-exposed Cblb-/- mice reverses their tumor rejection phenotype. Single cell RNA sequencing of in vitro differentiated Th9 cells from naïve T cells isolated from WT and Cblb-/- animals revealed the transcriptomic basis for increased Th9 cells differentiation. In summary, we here first establish IL-9 and Th9 cells as key anti-tumor executers in Cblb-/- animals. This knowledge may be helpful for future improvement of adoptive T cell therapies in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE173395 | GEO | 2022/04/30

REPOSITORIES: GEO

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Tumor rejection in Cblb-/- mice depends on IL-9 and Th9 cells

Project description:Tumor rejection in Cblb-/- mice depends on IL-9 and Th9 cells

| PRJNA725425 | ENA

Proteome analysis revealed the essential functions of protein phosphatase PP2A in the induction of Th9 cells

Project description:we performed proteome analysis of Th9 cells to understand the involvement of proteins that might be crucial for the anti-tumor functions of Th9 cells. Here we show for the first time a comprehensive proteomic analysis of murine Th0 and Th9 cells, which identified 1451 total proteins among which 1367 proteins were common. Further analysis revealed that 118 proteins were upregulated while 81 proteins were downregulated in Th9 cells. Pathway analysis suggested an abundance of phosphoproteins in the proteome of Th9 cells. Among upregulated phosphoproteins which showed to be involved in immune 34 system, Ppp2ca (catalytic subunit of protein phosphatase, PP2A) was found to be highly expressed in Th9 cells. Although the role of PP2A has been shown to regulate the differentiation and functions of Th1,Th2, Th17 and Tregs, its role in differentiation and functions of Th9 cells is not identified yet. Our results show for the first time that PP2A is required for the differentiation and anti-tumor functions of Th9 cells. PP2A inhibition leads to the suppression of IL-9 induction and the expression of key transcription factors of Th9 cells.

2021-09-09 | PXD019506 | Pride

The transcription factor BATF3 regulates the differentiation of TH9 cells and TH9-driven mucosal pathologies

Project description:T helper 9 (TH9) cells are important for the development of inflammatory and allergic diseases. The TH9 transcriptional network converge signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as strong inducer of mouse and human TH9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under TH9 and TH9-TL1A polarizing conditions. In vivo, using a T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3-/- TH9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role of BATF3 in TH9-induced mucosal inflammation.

2019-01-08 | GSE106926 | GEO

Study of new molecular mechanism for Th9 differentiation

Project description:Th9 cells are differentiated from naïve CD4+ T cells by T cell receptor (TCR) stimulation in the presence of the cytokines transforming growth factor-beta (TGF-b) and IL-4, but the molecular mechanisms by which signaling via these two cytokines control Il9 gene expression remain incompletely understood. We show here opposing functions of albumin site D-binding protein (DBP) and E2F8, an atypical member of the E2F family member of transcription factors , in controlling Th9 cell differentiation. Specifically, TGF-b and IL-4 signaling induced phosphorylation of the Serine 213 site in the linker region of the Smad3 protein (pSmad3L-Ser213) via the activation of phosphorylated MAPK p38 (p-p38). pSmad3L-Ser213, but not the phosphorylation of the C-terminal of SMAD3 (pSmad3C), was necessary and sufficient for Il9 gene transcription. We identified DBP and E2F8 as a potential activator and repressor, respectively, for Il9 gene transcription by analyzing the global chromatin accessibility and transcriptomes and discovered that pSmad3L-Ser213 was required for the increase in DBP expression but decreased E2F8 expressions during Th9 cell differentiation. We found that while DBP and E2F8 directly bound to the promoters of Il9 gene, DBP enhanced, but E2F8 suppressed, Il9 gene transcription in CD4+ T cells in response to TGF-b and IL-4 signaling, as revealed by functional gene loss- and gain-of-function studies. Notably, the Dbp-deficient and E2f8-deficient Th9 cells promoted and suppressed tumor growth, respectively, in experimental tumor models of melanoma and fibrosarcoma in mice. Importantly, DBP and E2F8 also exhibited opposing roles in regulating human TH9 differentiation in vitro. Thus, we have revealed a previously unrecognized molecular mechanism of Smad3 linker region-mediated opposing functions of DBP and E2F8 in Th9 differentiation.

2022-08-09 | GSE182472 | GEO

Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression

Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process. Genome-wide transcription factors mapping and binding of STAT5B and STAT6 in mouse polarized Th9 cells treated with or without blocking antibodies to IL-2 (anti-IL-2). RNA-Seq is conducted in WT and Il2-/- mice.

2014-02-20 | E-GEOD-41317 | biostudies-arrayexpress

Effect of IL-7 on CD4+ T cell and Th9 cells

Project description:We found that IL-7 pretreatment enhanced Th9 differentiation. To clarify the underlying mechanisms, we examine the gene expression profiles of CD4+ T cell and Th9 cells with or without IL-7 pretreatment. In Th9 cells, we found that Th9 related genes were greatly increased in IL-7 Th9 group, which demonstrated an enhanced Th9 differentiation. In CD4+ T cells, we found that IL-7 treatment resulted in a global gene expression change especially on chromatin remodeling related genes, which facilitated the entry of transcriptional factor to the Il9 promoter region and promoted Il9 transcription.

2017-02-06 | GSE86542 | GEO

TL1A signaling enhances the differentiation of TH9 cells and TH9-driven mucosal pathologies via BATF and BATF3 signaling pathways

Project description:The TNF family member TL1A (TNFSF15) co-stimulates several T helper subsets and promotes T cell-dependent models of inflammatory diseases, including inflammatory bowel diseases (IBD) and allergic lung disease. TL1A polymorphisms confer susceptibility to IBD and have been associated with disease severity. In this study, we identified TL1A as a strong inducer of TH9 cell differentiation in vitro. Mechanistically, TL1A induced NF-B signaling and down-stream STAT6 activation and facilitated cooperative binding of BATF, BATF3, and IRF4 to the Il9 promoter. In vivo, utilizing an adoptive T cell transfer model we demonstrated that TL1A promoted IL-9-dependent, TH9 cell-induced intestinal and lung inflammation and blocking anti-IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Our results demonstrate that TL1A promotes TH9 cell differentiation and function and define a role for IL-9 in TL1A-induced mucosal inflammation.

2019-01-08 | GSE60362 | GEO

Transcriptional profiling of human in vitro primed Th1, Th2, Th9 and Treg T cells

Project description:To test whether human in vitro primed Th9 cells recapitulate the core pathogenic Th2 cell phenotype, we differentiated naïve T cells into Th1 (IL-12), Th2 (IL-4), Th9 (IL-4+TGF-β), and iTreg (TGF-β). After 7 days transcriptomic profiling by bulk RNA-seq was performed.

2022-10-31 | E-MTAB-12199 | biostudies-arrayexpress

Gene expression profile at the single cell level of wild type and Cbl and Cblb knock-out organoids isolated from mouse intestional crypts.

Project description:Organoid grown from intestinal crypts of Cbl flox/flox; Cbl-bflox/flox; R26Cre ERT2 mice were in presence or absence of 4-hydroxy-tamoxifen to delete Cbl and Cblb. Single cell RNA sequencing were performed in these two conditions to undestand the change in cell populations due to Cbl and Cblb depeletion.

2023-07-01 | GSE236186 | GEO

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Project description:Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

2021-06-15 | GSE163056 | GEO

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