Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Cells ; 11(13)2022 06 23.
Article in English | MEDLINE | ID: mdl-35805096

ABSTRACT

Hematopoietic stem and progenitor cell (HSPC) maintenance and the differentiation of various lineages is a highly complex but precisely regulated process. Multiple signaling pathways and an array of transcription factors influence HSPC maintenance and the differentiation of individual lineages to constitute a functional hematopoietic system. Nuclear factor of activated T cell (NFAT) family transcription factors have been studied in the context of development and function of multiple mature hematopoietic lineage cells. However, until now their contribution in HSPC physiology and HSPC differentiation to multiple hematopoietic lineages has remained poorly understood. Here, we show that NFAT proteins, specifically NFATc1, play an indispensable role in the maintenance of HSPCs. In the absence of NFATc1, very few HSPCs develop in the bone marrow, which are functionally defective. In addition to HSPC maintenance, NFATc1 also critically regulates differentiation of lymphoid, myeloid, and erythroid lineage cells from HSPCs. Deficiency of NFATc1 strongly impaired, while enhanced NFATc1 activity augmented, the differentiation of these lineages, which further attested to the vital involvement of NFATc1 in regulating hematopoiesis. Hematopoietic defects due to lack of NFATc1 activity can lead to severe pathologies such as lymphopenia, myelopenia, and a drastically reduced lifespan underlining the critical role NFATc1 plays in HSPC maintenance and in the differentaion of various lineages. Our findings suggest that NFATc1 is a critical component of the myriad signaling and transcriptional regulators that are essential to maintain normal hematopoiesis.


Subject(s)
Bone Marrow Cells , Hematopoietic Stem Cells , Cell Differentiation , Cell Proliferation , Hematopoietic Stem Cells/metabolism , Transcription Factors/metabolism
2.
Cells ; 11(9)2022 04 20.
Article in English | MEDLINE | ID: mdl-35563702

ABSTRACT

The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4+CD25+Foxp3+ regulatory T (Treg) cells. In this study, we have investigated the role of NFATs in the thymic development of Treg cells in mice. We show that NFAT factors are dispensable for the development of Foxp3+ Treg cells in the thymus but are critical for the maintenance of both the phenotype and survival of Treg cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4+CD25+Foxp3+ but not the CD4+CD25-Foxp3+ fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced Treg population. We underscored this intriguing effect of NFAT on CD4+CD25+Foxp3+ Treg cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking Treg cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3+ Treg cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3+ Treg versus CD4+CD25- T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3+ Treg cells.


Subject(s)
Interleukin-2 , T-Lymphocytes, Regulatory , Animals , Forkhead Transcription Factors/metabolism , Interleukin-2/metabolism , Mice , Receptors, Interleukin-2/genetics , Receptors, Interleukin-2/metabolism , T-Lymphocytes, Regulatory/metabolism , TCF Transcription Factors/metabolism
3.
Nat Commun ; 7: 11841, 2016 06 17.
Article in English | MEDLINE | ID: mdl-27312418

ABSTRACT

NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1ß expression, preTCR-positive thymocytes express both Nfatc1ß and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1ß from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.


Subject(s)
Lymphopenia/immunology , NFATC Transcription Factors/immunology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Receptor, Notch3/immunology , T-Lymphocytes/immunology , Thymocytes/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cell Differentiation , Cell Lineage/genetics , Cell Lineage/immunology , Cell Survival , Gene Expression Regulation, Developmental/immunology , Lymphopenia/genetics , Lymphopenia/pathology , Mice , Mice, Knockout , NFATC Transcription Factors/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Promoter Regions, Genetic , Protein Isoforms/genetics , Protein Isoforms/immunology , Receptor, Notch3/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction , T-Lymphocytes/cytology , Thymocytes/cytology , Thymus Gland/cytology , Thymus Gland/immunology
4.
J Immunol ; 190(5): 2345-53, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23365084

ABSTRACT

NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/αA whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGFß. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/αA RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/αA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/αA and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-κB factors, together with anti-IgM, these signals also support the generation of NFATc1/αA. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level.


Subject(s)
B-Lymphocytes/drug effects , NFATC Transcription Factors/genetics , Th1 Cells/drug effects , Th2 Cells/drug effects , Animals , Antibodies/pharmacology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Proliferation/drug effects , Chromosomes, Artificial, Bacterial/genetics , Gene Expression/drug effects , Gene Expression/immunology , Genes, Reporter , Green Fluorescent Proteins , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , NF-kappa B/genetics , NF-kappa B/immunology , NFATC Transcription Factors/agonists , NFATC Transcription Factors/immunology , Promoter Regions, Genetic , Protein Isoforms/agonists , Protein Isoforms/genetics , Protein Isoforms/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...