The inducible transcription factor NFATc1 controls the survival of germinal center B lymphocytes (original) (raw)
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NFATc1 Induction in Peripheral T and B Lymphocytes
The Journal of Immunology, 2013
NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/aA 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 TGFb. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/aA 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/aA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/aA 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-kB factors, together with anti-IgM, these signals also support the generation of NFATc1/aA. 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.
Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation
Frontiers in immunology, 2018
In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is thegene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of thegene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered withRNA expression, LPS-mediated differentiation of splenic B cells to plasmablastsand reduce...
NF-κB factors control the induction of NFATc1 in B lymphocytes
European journal of immunology, 2014
In peripheral lymphocytes, the transcription factors (TFs) NF-κB, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-κB factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of κB-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-κB seem neither to interact nor to collaborate. We show here that NF-κB1/p50 and c-Rel, the most prominent NF-κB proteins in BCR-induced splenic B cells, control the induction of NFATc1/αA, a prominent short NFATc1 isoform. In part, this is mediated through two composite κB/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/αA by BCR signals. In...
Autoregulation of NFATc1/A Expression Facilitates Effector T Cells to Escape from Rapid Apoptosis
Immunity, 2002
in particular, the expression of lymphokines, Institute of Pathology such as IL-2, IL-3, IL-4, IL-5, and IFN␥. However, lympho-2 Institute of Virology and Immunobiology kine promoters are not the only targets which are bound University of Wuerzburg and controlled by NFATc1 and NFATc2. Further target D-97080 Wuerzburg promoters for NFATs are the p21 Waf1 , the CD40 ligand, 3 Institute of Immunology and CD95 ligand promoters (Holtz-Heppelmann et al., University of Mainz 1998; Latinis et al., 1997; Santini et al., 2001; Tsytsykova D-55101 Mainz et al., 1996), indicating that in addition to effector func-Germany tion NFATs are also involved in the control of cell cycle 4 Biomedical Research and Study Center and, in particular, apoptosis of T lymphocytes. Activa-University of Latvia tion-induced cell death (AICD) of lymphocytes is a par-LV-1067 Riga ticular form of apoptosis which is of pivotal importance Latvia for the termination of the immune response and, therefore, the homeostasis of the immune system. One important route of AICD is the activation through so-called Summary death receptors, in particular, of CD95 and TNF-receptor I. Their stimulation by CD95 ligand or TNF␣ leads to the Threshold levels of individual NFAT factors appear to activation of a caspase cascade and, in turn, to cleavage be critical for apoptosis induction in effector T cells. of death substrates and, finally, to apoptosis of T cells In these cells, the short isoform A of NFATc1 is induced (see, e.g., Schmitz et al., 2000). Both the CD95 ligand to high levels due to the autoregulation of the NFATc1 and TNF␣ promoter contain multiple NFAT sites (Falvo promoter P1 by NFATs. P1 is located within a CpG et al., 2000; Li-Weber et al., 1999), suggesting that island in front of exon 1, represents a DNase I hyper-NFATs are major regulators of AICD of T cells. sensitive chromatin site, and harbors several sites for NFATc1 and NFATc2 share 72% sequence homology binding of inducible transcription factors, including a in their RSDs and act similarly in functional assays. Howtandemly arranged NFAT site. A second promoter, P2, ever, inactivation of either of the two genes resulted in before exon 2, is not controlled by NFATs and directs markedly divergent mutant phenotypes. Due to defects synthesis of the longer NFATc1/BϩC isoforms. Conin the development of cardiac valves and septa, trary to other NFATs, NFATc1/A is unable to promote NFATc1-deficient mouse embryos die in utero before apoptosis, suggesting that NFATc1/A enhances efday 14 of gestation (de la Pompa et al., 1998; Ranger fector functions without promoting apoptosis of efet al., 1998a) whereas no such defect in embryonic defector T cells. velopment was observed in NFATc2-deficient mice. However, lymphocytes in NFATc2 Ϫ/Ϫ mice older than 3 Introduction months develop a hyperproliferative syndrome which is reflected by a moderate increase in size of peripheral NFAT (nuclear factor of activated T cells) proteins belong lymphoid organs (Hodge et al., 1996; Schuh et al., 1998; to a family of transcription factors which share a com-Xanthoudakis et al., 1996). This appears to be caused mon DNA binding domain of approximately 300 amino by distinct defects in AICD (Schuh et al., 1998), probably acids (aa). This domain is very similar in its conformation due to an impaired expression of CD95 ligand (Hodge to the Rel DNA binding domain of Rel/NF-B factors et al., 1996). This phenotype was found to be accelerated and, therefore, was designated as Rel similarity domain in mice deficient for both NFATc2 and NFATc3 (Ranger (RSD; for reviews see Rao et al., 1997; Serfling et al., et al., 1998c). In contrast, peripheral NFATc1 Ϫ/Ϫ T cells 2000). Among the four genuine NFAT factors, NFATc1, from RAG Ϫ/Ϫ mice show an impaired proliferation but NFATc2, NFATc3, and NFATc4, the RSDs exhibit apno apparent defects in apoptosis (Ranger et al., 1998b; proximately 70% sequence homology and about 40% Yoshida et al., 1998). Lymphocytes doubly deficient for with a fifth protein, designated as NFAT5 (Lopez-Rodri-NFATc1 and NFATc2 exhibit a complete loss of IL-2 and guez et al., 1999). The nuclear translocation of genuine IL-4 production but-similar to NFATc2 Ϫ/Ϫ lympho-NFAT factors but not of NFAT5 is regulated by the Ca 2ϩ / cytes-a hyperproliferative syndrome which is characterized by high IgG1 and IgE serum levels and an increase in activation markers (Peng et al., 2001). These
NFATc1/αA: The other Face of NFAT Factors in Lymphocytes
Cell Communication and Signaling, 2012
In effector T and B cells immune receptor signals induce within minutes a rise of intracellular Ca ++ , the activation of the phosphatase calcineurin and the translocation of NFAT transcription factors from cytosol to nucleus. In addition to this first wave of NFAT activation, in a second step the occurrence of NFATc1/αA, a short isoform of NFATc1, is strongly induced. Upon primary stimulation of lymphocytes the induction of NFATc1/αA takes place during the G1 phase of cell cycle. Due to an auto-regulatory feedback circuit high levels of NFATc1/αA are kept constant during persistent immune receptor stimulation. Contrary to NFATc2 and further NFATc proteins which dampen lymphocyte proliferation, induce anergy and enhance activation induced cell death (AICD), NFATc1/αA supports antigenmediated proliferation and protects lymphocytes against rapid AICD. Whereas high concentrations of NFATc1/αA can also lead to apoptosis, in collaboration with NF-κB-inducing co-stimulatory signals they support the survival of mature lymphocytes in late phases after their activation. However, if dysregulated, NFATc1/αA appears to contribute to lymphoma genesis andas we assumeto further disorders of the lymphoid system. While the molecular details of NFATc1/αA action and its contribution to lymphoid disorders have to be investigated, NFATc1/αA differs in its generation and function markedly from all the other NFAT proteins which are expressed in lymphoid cells. Therefore, it represents a prime target for causal therapies of immune disorders in future.
The American Journal of Pathology, 2008
The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T-and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin's lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and Sp1 factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 P1 promoter, which we detected in all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 pro-moter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing. (Am J Pathol
Control of lymphocyte development by nuclear factor-?B
Nat Rev Immunol, 2005
The transcription factor nuclear factor-κB (NF-κB) is essential for both innate and adaptive immunity. It is crucial for the initial responses of sentinel cells to pathogens, as well as for the subsequent events that lead to T-and B-cell-mediated antigen-specific defence. The role of NF-κB in acute innate immune responses is evolutionarily conserved at least as far back as insects, in which NF-κB is responsible for the induction of nearly all responses to pathogens. Recently, NF-κB has also been recognized to be crucial for the development of several mammalian haematopoietic cell lineages and for the formation of secondary lymphoid-organ structures. In this article, we focus on the cell-autonomous roles of NF-κB in developing T and B cells, in which the main, but not exclusive, function of NF-κB is to ensure survival. The precise nature of NF-κB activity, as well as how it is activated and which genes it regulates, is context dependent, varying with the developmental stage and the initiating signal.