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Calcineurin B in CD4 T cells prevents autoimmune colitis by by negatively regulating the JAK/STAT pathway

ABSTRACT: Nuclear factor of activated T-cells (NFAT) are a family of transcription factors, which are regulated by the calcium-sensing protein calmodulin and protein phosphatase Calcineurin. The different NFAT family members can have overlapping functions but also are now known to exhibit distinct functions in T cells and can influence host tolerance. In the current study, we investigated for the first time the role played by the calcineurin B (Cnb1) signaling in CD4 T cells. We generated mice that lack selectively Cnb1 in CD4 T cells (Cnb1CD4 mice) and analyzed the immune phenotype during the ageing and in vitro studies. Disruption of CnB signal in CD4 T cells was associated with an increase of IFNγ- and IL-17-secreting cells. Antibiotic treatment reverted the spontaneous intestinal inflammation observed in Cnb1CD4 mice, indicating that microbiota is the main factor involved in colitis onset. Our data indicate that Cnb1 pathway in CD4 T cells is fundamental to maintain immune homeostasis in the colon

ORGANISM(S): Mus musculus

PROVIDER: GSE101785 | GEO | 2018/08/01

REPOSITORIES: GEO

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Calcineurin-dependent transcriptome in ICN1 (activated NOTCH1)-induced T cell acute lymphoblastic leukemia (T-ALL)

Project description:Activated NOTCH1 induces T-ALL in mice when transduced in bone marrow (BM) cells. T-ALL cells activate the calcineurin/NFAT pathway in vivo (Medyouf H. et al. Nat Med 2007 [PMID 17515895]). Through appropriate crosses, mouse ICN1-induced T-ALL were generated that include a ROSCreERT2 transgene and 2 copies of a CnB1 floxed alleles. Cohorts of secondary recipient mice were injected with these T-ALL cells, and when becoming leukemic, divided into 2 subgroups. Group 1 was treated with Tamoxifen (TAM), resulting in CnB1 gene deletion and inactivation of calcineurin. Group 2 was treated with carrier solvent (corn OIL), thus maintaining CnB1 and calcineurin activity. RNAs were extracted from flow cytometry-sorted leukemic cells. Details in Gachet S. et al. Leukemia 2013 (PMID 23689515).

2014-08-09 | E-GEOD-60258 | biostudies-arrayexpress

Calcineurin-dependent transcriptome in ICN1 (activated NOTCH1)-induced T cell acute lymphoblastic leukemia (T-ALL)

2014-08-09 | GSE60258 | GEO

Calcineurin/NFAT signaling inhibits myeloid hematopoiesis in mice.

Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates

2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress

Calcineurin/NFAT signaling inhibits myeloid hematopoiesis in mice.

2011-10-01 | GSE29094 | GEO

Impaired calcineurin signaling in dendritic cells and macrophages increases susceptibility to aspergillosis through pentraxin-3 downregulation

Project description:Treatment of post-transplant patients with immunosuppressive drugs targeting the calcineurin-NFAT pathway, such as Cyclosporine A or Tacrolimus, are commonly associated with a higher incidence of opportunistic infections, such as Aspergillus fumigatus, which can lead to severe life-threating conditions. A component of the A. fumigatus cell wall, β-glucan, is recognized by dendritic cells via the Dectin-1 receptor, triggering downstream signaling that leads to calcineurin-NFAT binding, NFAT translocation, and transcription of NFAT-regulated genes. Here, we address the question of whether calcineurin signaling in CD11c-expressing cells, such as DCs, has a specific role in the innate control of A. fumigatus. Impairment of calcineurin in CD11c-expressing cells (CD11ccrecnb1loxP) significantly increased susceptibility to systemic A. fumigatus infection and to intranasal infection in irradiated mice undergoing bone marrow transplant. Global expression profiling of bone marrow-derived DCs identified calcineurin-regulated processes in the immune response to infection, including expression of pentraxin-3, an important anti-fungal defense protein. These results suggest that calcineurin inhibition directly impairs important immunoprotective functions of myeloid cells, as shown by the higher susceptibility of CD11ccrecnbloxP mice in models of systemic and invasive pulmonary aspergillosis, including after allogeneic bone marrow transplantation. These findings are relevant to the clinical management of transplant patients with severe Aspergillus infections.

2016-12-31 | GSE71936 | GEO

Granulocyte-monocyte progenitor cell cycle regulation occurs through calcium flux and calcineurin-NFAT signaling via Flt3-L

Project description:Complex regulatory mechanisms control continuous maintenance of myeloid progenitors and renewal of differentiated cells. Transcription factors play a important role in these processes. Here we report that the activation the calcineurin-NFAT signaling pathway inhibit the proliferation of myeloid granulocyte-monocyte progenitor (GMP). Myeloid progenitor subtypes possessed different susceptibilities to Ca2+ flux induction and consequently differential engagement of the calcineurin-NFAT pathway. This study show that inhibition of the calcineurin-NFAT pathway enhanced proliferation of GMPs both in vivo and in vitro. The calcineurin-NFAT signaling in GMPs is initiated through Flt3-L. The inhibition of the calcineurin-NFAT pathway altered the expression of the cell cycle regulation genes CDK4, CDK6, and CDKN1A, thus enabling faster cell cycle progression. The extensive use of NFAT inhibitors in the clinic should take into account that, in addition to the immunosuppression role in lymphoid cells, these NFAT inhibitors also affect the maintenance of the myeloid compartment. Microarray technology was used to understand the effects of NFAT inhibitors on C-kit enriched lineage negative cells.

2014-12-31 | GSE47208 | GEO

Identification of calcineurin-dependent gene expression changes in response to chronic CaCl2 stress

Project description:Gene expression was quantified in S. cerevisae cells over a time course of three days of CaCl2 treatment to activate calcineurin. Wild type (WT) and cnb1 mutant strains were compared to allow the identification of calcineurin-dependent gene expression changes. We show that mitochondrial genes are downregulated, and ribosome biogenesis genes are upregulated, in both geneotypes over time.

2024-03-19 | GSE254551 | GEO

Identification of calcineurin-dependent, Crz1-independent gene expression changes in response to chronic CaCl2 stress

Project description:Gene expression was quantified in S. cerevisae cells over a time course of three days of CaCl2 treatment to activate calcineurin. crz1 and crz1 cnb1 mutant strains were compared to allow the identification of calcineurin-dependent gene expression changes that are independent of the downstream transcription factor Crz1. We show that mitochondrial genes are downregulated in both geneotypes over time. Additionally, genes that promote glutathione biosynthesis are upregulated in cells that express calcineurin.

2024-03-19 | GSE254552 | GEO

Identification of calcineurin-dependent, Crz1-independent gene expression changes in response to chronic KCl stress

Project description:Gene expression was quantified in S. cerevisae cells after 48 hours of treatment with KCl. crz1 and crz1 cnb1 mutant strains were compared to allow the identification of calcineurin-dependent gene expression changes that are independent of the downstream transcription factor Crz1. We find that calcineurin has very little effect on gene expression in response to KCl.

2024-03-19 | GSE254554 | GEO

Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma

Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common form of lymphoma. We could show that in DLBCL cell lines the transcription factor NFAT is constitutively activated and drives the survival of a DLBCL subset. Aim of the analysis was to identify NFAT target genes in a NFAT-dependent (HBL-1) or -independent (HT) DLBCL cell line. To block NFAT activity, the DLBCL cells were treated with the calcineurin inhibitor cyclosporin A (CsA) up to 48 h. With this approach, we identified several survival-related NFAT target genes in HBL-1 cells that might explain the toxic effects of calcineurin inhibitors.

2019-11-23 | GSE140882 | GEO

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