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1.
iScience ; 26(3): 106234, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36926655

RESUMO

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αß thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells.

3.
Cell Mol Immunol ; 16(5): 508-520, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29907883

RESUMO

B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.


Assuntos
Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Fatores de Transcrição NFATC/metabolismo , Células Precursoras de Linfócitos B/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Interleucina-7/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo
4.
Oncotarget ; 9(11): 9632-9644, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29515759

RESUMO

The role of NFAT family transcription factors in erythropoiesis is so far unknown, although their involvement has been suggested previously. We have shown recently that Il2-/- mice develop severe anemia due to defects in KLF1 activity during BM erythropoiesis. Although, KLF1 activity is indispensable for erythropoiesis, the molecular details of Klf1 expression have not yet been elucidated. Here we show that an enhanced NFATc1 activity induced by increased integrin-cAMP signaling plays a critical role in the dysregulation of Klf1 expression and thereby cause anemia in Il2-/- mice. Interestingly, enhanced NFATc1 activity augmented apoptosis of immature erythrocytes in Il2-/- mice. On the other hand, ablation of NFATc1 activity enhanced differentiation of Ter119+ cells in BM. Restoring IL-2 signaling in Il2-/- mice reversed the increase in cAMP-NFAT signaling and facilitated normal erythropoiesis. Altogether, our study identified an NFAT-mediated negative signaling axis, manipulation of which could facilitate erythropoiesis and prevent anemia development.

5.
Oncotarget ; 8(18): 29625-29642, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28415569

RESUMO

The role of IL-2 in HSC maintenance is unknown. Here we show that Il2-/- mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2-/- mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2-/- mice shows that the IL-2-Treg cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of Treg activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring Treg population successfully rescued HSC maintenance in Il2-/- mice, preventing IFN-γ activity could do the same even in the absence of Treg cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Interleucina-2/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Biomarcadores , Autorrenovação Celular/genética , Hematopoese/genética , Hematopoese/imunologia , Imunofenotipagem , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Transdução de Sinais , Linfócitos T Reguladores/imunologia
7.
Nat Commun ; 7: 11724, 2016 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-27222343

RESUMO

Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.


Assuntos
Linfócitos B/imunologia , Interleucina-10/metabolismo , Fatores de Transcrição NFATC/fisiologia , Aminoquinolinas/farmacologia , Animais , Linfócitos B/metabolismo , Modelos Animais de Doenças , Imiquimode , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/metabolismo , Transdução de Sinais
8.
Eur J Immunol ; 46(3): 634-46, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631626

RESUMO

The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca(++) /CN/NFAT, Ca(++) /CN/cofilin, Ca(++) /CN/BAD, and NF-κB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1ß isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/ß proteins represent the most prominent NFATc1 isoforms. NFATc1/ß ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/ß proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients.


Assuntos
Macrófagos Peritoneais/metabolismo , Fatores de Transcrição NFATC/imunologia , Fatores de Transcrição NFATC/fisiologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CCR2/agonistas , Receptores CCR2/imunologia , Saccharomyces cerevisiae/imunologia , Animais , Calcineurina/metabolismo , Inibidores de Calcineurina , Quimiocina CCL2/genética , Quimiocina CCL7/genética , Macrófagos Peritoneais/microbiologia , Camundongos , Proteínas Quimioatraentes de Monócitos/genética , Monócitos/imunologia , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/deficiência , Fatores de Transcrição NFATC/genética , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Regiões Promotoras Genéticas , Isoformas de Proteínas , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-6/genética
9.
Eur J Immunol ; 45(12): 3362-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26404745

RESUMO

Mice deficient in IL-2 signaling develop severe anemia indicating a defect in erythropoiesis. However, why deficiency in IL-2, an essential growth factor for lymphocytes, or in IL-2 signaling components should result in defective erythropoiesis is unclear. Here, we have analyzed the mechanism of IL-2 signaling deficiency induced anemia in mice and show that IL-2 plays an indispensable role in bone marrow (BM) erythropoiesis via maintenance of regulatory T (Treg) cells. In absence of IL-2 signaling, IFN-γ produced by the activated T cells suppressed klf1 expression, resulting in an early block in erythrocyte differentiation. Anemia, in IL-2 or IL-2 signaling deficient mice always developed prior to the manifestation of other autoimmune complications such as colitis, suggesting that anemia in these mice might be a contributing factor in inducing other pathological complications in later stages. Our study shows, how essential cytokines of lymphoid cells could exert critical influence on the development of erythrocytes and thus expanding our understanding of the complex regulation of hematopoiesis in the BM. Besides, our findings might facilitate the use of IL-2 and anti-IFN-γ as a clinical remedy against anemia that arise in cancer patients following radiotherapy or chemotherapy, a context which simulates the situation of IL-2 deficiency.


Assuntos
Medula Óssea/fisiologia , Interleucina-2/fisiologia , Anemia/prevenção & controle , Animais , Eritropoese , Proteínas de Homeodomínio/fisiologia , Interferon gama/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-7/fisiologia , Linfócitos T/fisiologia
10.
Eur J Immunol ; 44(11): 3392-402, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25179582

RESUMO

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 concert with coreceptor signals that induce NF-κB factors, BCR signaling induces a persistent generation of NFATc1/αA. These data suggest a tight connection between NFATc1 and NF-κB induction in B lymphocytes contributing to the effector function of peripheral B cells.


Assuntos
Linfócitos B/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Proteínas Proto-Oncogênicas c-rel/metabolismo , Animais , Sítios de Ligação , Galinhas , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/genética , Fatores de Transcrição NFATC/biossíntese , Regiões Promotoras Genéticas , Ligação Proteica , Isoformas de Proteínas/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelB/genética
11.
Front Immunol ; 5: 21, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24550910

RESUMO

In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca(++), the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.

12.
Nat Immunol ; 14(2): 127-35, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263556

RESUMO

Interleukin 7 (IL-7) has a critical role in the development of early CD4(-)CD8(-) double-negative (DN) thymocytes. Although the transcription factor STAT5 is an important component of IL-7 signaling, differences in the phenotypes of mice deficient in STAT5, IL-7, IL-7 receptor alpha (IL-7rα) or the kinase Jak3 suggest the existence of STAT5-independent IL-7 signaling. Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. This NFAT-activation pathway was critical for the survival and development of DN thymocytes, as deficiency in NFATc1 blocked thymocyte development at the DN1 stage, leading to T cell lymphopenia. In addition, our results demonstrated a cooperative function for NFATc1 and STAT5 in guiding thymocyte development in response to IL-7 signals.


Assuntos
Interleucina-7/genética , Fatores de Transcrição NFATC/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais/imunologia , Timócitos/citologia , Animais , Antígenos CD4/genética , Antígenos CD4/imunologia , Antígenos CD8/genética , Antígenos CD8/imunologia , Diferenciação Celular , Regulação da Expressão Gênica , Interleucina-7/imunologia , Janus Quinase 3/genética , Janus Quinase 3/imunologia , Linfopenia/imunologia , Linfopenia/patologia , Camundongos , Camundongos Transgênicos , Fatores de Transcrição NFATC/deficiência , Fosforilação , Regiões Promotoras Genéticas , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT5/imunologia , Timócitos/imunologia , Transcrição Gênica
13.
J Exp Med ; 208(4): 823-39, 2011 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-21464221

RESUMO

By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell-independent type II antigens, as well as IgG3(+) plasmablast formation. Mice bearing NFATc1(-/-) B cells harbor twofold more interleukin 10-producing B cells. NFATc1(-/-) B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1(-/-) B cells are caused by decreased BCR-induced Ca(2+) flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca(2+)-dependent Cn-NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.


Assuntos
Linfócitos B/imunologia , Calcineurina/fisiologia , Fatores de Transcrição NFATC/fisiologia , Transdução de Sinais/fisiologia , Baço/imunologia , Animais , Cálcio/metabolismo , Switching de Imunoglobulina , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos B/fisiologia , Linfócitos T/fisiologia
14.
J Immunol ; 177(7): 4567-76, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16982894

RESUMO

Protein kinase B (PKB), an Ag receptor activated serine-threonine kinase, controls various cellular processes including proliferation and survival. However, PKB function in thymocyte development is still unclear. We report PKB as an important negative regulator of the calcineurin (CN)-regulated transcription factor NFAT in early T cell differentiation. Expression of a hyperactive version of CN induces a profound block at the CD25+CD44- double-negative (DN) 3 stage of T cell development. We correlate this arrest with up-regulation of Bcl-2, CD2, CD5, and CD27 proteins and constitutive activation of NFAT but a severe impairment of Rag1, Rag2, and intracellular TCR-beta as well as intracellular TCR-gammadelta protein expression. Intriguingly, simultaneous expression of active myristoylated PKB inhibits nuclear NFAT activity, restores Rag activity, and enables DN3 cells to undergo normal differentiation and expansion. A correlation between the loss of NFAT activity and Rag1 and Rag2 expression is also found in myristoylated PKB-induced CD4+ lymphoma cells. Furthermore, ectopic expression of NFAT inhibits Rag2 promoter activity in EL4 cells, and in vivo binding of NFATc1 to the Rag1 and Rag2 promoter and cis-acting transcription regulatory elements is verified by chromatin immunoprecipitation analysis. The regulation of CN/NFAT signaling by PKB may thus control receptor regulated changes in Rag expression and constitute a signaling pathway important for differentiation processes in the thymus and periphery.


Assuntos
Calcineurina/metabolismo , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/citologia , Animais , Western Blotting , Calcineurina/imunologia , Proteínas de Ligação a DNA/imunologia , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Proteínas de Homeodomínio/imunologia , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Fatores de Transcrição NFATC/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/citologia , Timo/crescimento & desenvolvimento , Transfecção
15.
J Immunol ; 172(8): 4812-20, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15067058

RESUMO

T cell activation leads to the induction of the transcription factors of the NFAT and NF-kappa B families, important regulators of T cell activation and function. In this study we demonstrate that TCR/CD3-stimulated T cells from mice expressing a constitutively active form of protein kinase B (myr PKB alpha) lack significant nuclear accumulation/shuttling of NFATc1 and NFATp as well as NF-kappa Bp65 and RelB proteins. Notably, despite this deficit in nuclear NFAT and NF-kappa B proteins, myr PKB T cells show lower activation threshold for proliferation, enhanced cell cycle progression and increased production of Th1 and Th2 cytokines similar to signals provided by CD28 costimulation. The enhanced T cell response correlates with increased expression of cyclins D3 and B1 and cytokine-induced Src homology 2 protein, and inactivation of the forkhead transcription factor FKHR. In addition, coimmunoprecipitation studies indicate a direct regulation of NFATc1 by active PKB. Together, our results demonstrate that the positive regulatory role of myr PKB on TCR responsiveness, subsequent cell division, and effector function is linked to a negative regulatory mechanism on the nuclear accumulation/shuttling of NFAT and NF-kappa B proteins.


Assuntos
Adjuvantes Imunológicos/fisiologia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/metabolismo , Proteínas Nucleares , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/fisiologia , Fatores de Transcrição/metabolismo , Adjuvantes Imunológicos/genética , Adjuvantes Imunológicos/metabolismo , Animais , Antígenos CD28/fisiologia , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Ciclo Celular/imunologia , Divisão Celular/imunologia , Ciclosporina/farmacologia , Citocinas/biossíntese , Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/antagonistas & inibidores , Fatores de Transcrição NFATC , Sinais de Localização Nuclear/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/antagonistas & inibidores
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