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1.
Artigo em Inglês | MEDLINE | ID: mdl-31405607

RESUMO

BACKGROUND: B-cell receptor (BCR) signaling, combined with CD19 and CD21 signals, imparts specific control of B-cell responses. Dedicator of cytokinesis protein 2 (DOCK2) is critical for the migration and motility of lymphocytes. Although absence of DOCK2 leads to lymphopenia, little is known about the signaling mechanisms and physiologic functions of DOCK2 in B cells. OBJECTIVE: We sought to determine the underlying molecular mechanism of how DOCK2 regulates BCR signaling and peripheral B-cell differentiation. METHODS: In this study we used genetic models for DOCK2, Wiskott-Aldrich syndrome protein (WASP), and lymphoid enhancer-binding factor 1 deficiency to study their interplay in BCR signaling and B-cell differentiation. RESULTS: We found that the absence of DOCK2 led to downregulation of proximal and distal BCR signaling molecules, including CD19, but upregulation of SH2-containing inositol 5 phosphatase 1, a negative signaling molecule. Interestingly, DOCK2 deficiency reduced CD19 and CD21 expression at the mRNA and/or protein levels and was associated with reduced numbers of marginal zone B cells. Additionally, loss of DOCK2 reduced activation of WASP and accelerated degradation of WASP, resulting into reduced actin accumulation and early activation of B cells. Mechanistically, the absence of DOCK2 upregulates the expression of lymphoid enhancer-binding factor 1. These differences were associated with altered humoral responses in the absence of DOCK2. CONCLUSIONS: Overall, our study has provided a novel underlying molecular mechanism of how DOCK2 deficiency regulates surface expression of CD21, which leads to downregulation of CD19-mediated BCR signaling and marginal zone B-cell differentiation.

2.
J Immunol ; 203(2): 323-327, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175159

RESUMO

The differentiation of memory CD8+ T cells is critical to the long-term cellular immunity. The transcription factor BCL6 has been reportedly important for the generation and maintenance of memory CD8+ T cells; however, using the newly established BCL6 conditional knockout mouse model, we demonstrate that BCL6 is dispensable for the maintenance of established memory CD8+ T cell pool, although BCL6 is still required for the generation of CD8+ memory precursors upon acute viral infection. In addition, BCL6 promotes the expression of TCF-1 via directly binding to the Tcf7 (gene symbol for TCF-1) allele in CD8+ memory precursors and forced expression of TCF-1 restores the generation of BCL6-deficient memory precursors. Thus, our findings clarify that BCL6 is dispensable for the maintenance of memory CD8+ T cells, but functions as an important upstream of TCF-1 to regulate the generation of memory precursors in acute viral infection.

3.
Biomater Sci ; 7(6): 2533-2544, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30968875

RESUMO

Cytotoxic CD8+ T cells (CTLs) are crucial for controlling intracellular pathogens as well as cancer. However, how to promote the cytotoxic activity of CTL cells in vitro and in vivo remains largely unknown. On the other hand, ceria nanoparticles (CNPs) are widely used in biomedical fields, but the role of CNPs in CTL cells is still unclear. In this study, we found that the activated antigen-specific (P14) and nonspecific CD8+ T cells with CNP treatment both produced more cytokines, including interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α), and released more effector molecules, such as granzyme B and perforin, and then exhibited higher killing activity of P14 cells in vitro and stronger viral clearance capacity of CTL cells in vivo. Mechanistically, the activated P14 cells with CNP treatment inhibited the production of reactive oxygen species, and therefore promoted the activity of NF-κB signaling. Importantly, while the P14 cells were simultaneously treated by IMD-0354, a specific inhibitor of NF-κB signaling, the increases of IL-2 and TNF-α productions and granzyme B and perforin releases were remedied, and the P14 cells eventually exhibited the natural killing activity in vitro. Thus, our results demonstrated that CNP treatment promoted the cytotoxic activity of CTL cells and provide new ideas in the usage of CNPs and fascinating pharmacological potentials for clinical application, especially cancer immunotherapy.

4.
Front Immunol ; 10: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814995

RESUMO

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.

5.
Cell Mol Immunol ; 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842630

RESUMO

Epigenetic modifications to histones dictate the differentiation of naïve CD4+ T cells into different subsets of effector T helper (TH) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of TH1, TH2 and regulatory T (Treg) cells. However, whether and how EZH2 regulates follicular helper T (TFH) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells. Ablation of EZH2 in LCMV-specific CD4+ T cells leads to a selective impairment of early TFH cell fate commitment, but not late TFH differentiation or memory TFH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs TFH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.

6.
Sci Total Environ ; 665: 61-68, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30772579

RESUMO

Exposure to airborne microbes (AM) can affect the human microbiome and has various consequences for human health. Investigating the profiles of AM and the potential bacterial pathogens within, along with the factors influencing their community, is pivotal for understanding the impact of AM on human health. In this study, we collected AM during spring and summer from 11 sites with various levels of urbanization in the city of Xiamen, China. Bacterial community compositions of the AM were determined based on 16S rRNA gene amplicon sequencing. Firmicutes and Proteobacteria were the predominating phyla in the airborne bacterial communities, and a higher (P < 0.05) diversity of AM was found during the summer as compared to the spring. Significant differences in the community structure of the AM and the potential bacterial pathogens within airborne microbes were observed among the seasons and the sites with different levels of urbanization. Increases and/or decreases in the abundance of Bacillus and Acinetobacter could explain a major part of the variations in the AM community compositions. The proportion of potential bacterial pathogens during the summer was significantly higher (P < 0.01) than in the spring, and the relative abundance of several bacterial pathogens (i.e. Burkholderia multivoran, Enterococcus faecium and Streptococcus thermophilus) related to human diseases (39.8% of total pathogens on average) increased with increasing urbanization levels, suggesting that urbanization can increase the AM-associated human health risk.


Assuntos
Microbiologia do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Monitoramento Ambiental , Microbiota , Bactérias , China , Cidades , Clima , Firmicutes , Proteobactérias , RNA Ribossômico 16S , Estações do Ano , Urbanização
7.
J Trace Elem Med Biol ; 52: 126-135, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732873

RESUMO

Cerium and cerium containing materials have been drawing increasing attentions in industrial and biomedical applications in recent decades. The increased applications of cerium have also increased the risk of human body exposed to cerium ions. Due to its similar ionic radius to calcium(II), cerium(III) have found mainly deposited in the skeletal system. However, the effects of cerium(III) on the bone metabolism homeostasis remain poorly understood. In the present study, the effect of cerium(III) on the osteoclastogenesis which plays a pivotal role in bone metabolism homeostasis was investigated. Cerium(III) could enhance the expression and activity of NADPH oxidase1 (Nox1) leading to the elevation of intracellular reactive oxygen species (ROS) level. The augmentation of ROS level activated the RANKL dependent osteoclasts differentiation pathways resulted in the promotion of osteoclastogenesis, while anions associated with cerium(III) cation have no effects on the differentiation of osteoclasts. The cerium(III) activated osteoclasts exhibited enhanced bone resorption capability. These results provided fundamental information for understanding the potential effects of cerium(III) on the metabolism homeostasis of skeletal system which is of great reference value for future biomedical applications of cerium salts.


Assuntos
Cério/farmacologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Íons/farmacologia , Camundongos , Osteoclastos/metabolismo , Células RAW 264.7
8.
ACS Sens ; 3(11): 2385-2393, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30387341

RESUMO

Though the chemical origin of a metal oxide gas sensor is widely accepted to be the surface reaction of detectants with ionsorbed oxygen, how the sensing material transduces the chemical reaction into an electrical signal (i.e., resistance change) is still not well-recognized. Herein, the single ZnO NW is used as a model to investigate the relationship between the microstructure and sensing performance. It is found that the acetone responses arrive at the maximum at the NW diameter ( D) of ∼110 nm at the D range of 80 to 400 nm, which is temperature independent in the temperature region of 200 °C-375 °C. The electrical properties of the single NW field effect transistors illustrate that the electron mobility decreases but electron concentration increases with the D ranging from ∼60 nm to ∼150 nm, inferring the good crystal quality of thinner ZnO NWs and the abundant crystal defects in thicker NWs. Subsequently, the surface charge layer ( L) is calculated to be a constant of 43.6 ± 3.7 nm at this D range, which cannot be explained by the conventional D- L model in which the gas-sensing maximum appears when D approximates 2 L. Furthermore, the crystal defects in the single ZnO NW are probed by employing the microphotoluminescence technique. The mechanism is proposed to be the compromise of the two kinds of crystal defects in ZnO (i.e., more donors and fewer acceptors favor the gas-sensing performance), which is again verified by the gas sensors based on the NW contacts.

9.
Huan Jing Ke Xue ; 39(6): 2600-2606, 2018 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-29965614

RESUMO

Many cities are located in the downstream areas of rivers. Rapid urbanization may result in drastic changes in the urban river ecosystem. Antibiotic resistant genes (ARGs) are considered to be emerging environmental pollutants, which may do harm to the health of humans and may pose a potential risk for urban ecological safety by the dissemination and enrichment of ARGs in urban rivers. In this study, a high-throughput quantitative PCR technique was used to investigate the diversity and abundance of ARGs at three sites in Lianjiang County and the estuary of the Aojiang River, Fujian Province. The results show the abundance of ARGs in the downstream urban area of Lianjiang County (3.9×1010 copies·L-1) is significantly higher than upstream of the urban area and the estuary of the Aojiang River. A total of 129 ARGs are detected in the downstream urban area, which is higher than in the upstream and the estuary. The results also suggest that ARGs are persistent and not easy to reduce in the natural river following the occurrence of ARGs and indicated that the urban river is an important reservoir of ARGs.

10.
Front Immunol ; 9: 1127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875775

RESUMO

Follicular helper CD4+ T (TFH) cells are critical for optimal B-cell-mediated humoral immunity by initiating, fueling, and sustaining germinal center reactions. The differentiation of TFH cells relies on multiple intrinsic and extrinsic factors; however, the details by which these factors are integrated to coordinate TFH differentiation are largely unknown. In this study, using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) viral infection, we demonstrate that mTOR complex 2 (mTORC2) kinase integrates TCR signaling and ICOS-mediated co-stimulation to promote late differentiation and functional maturation of virus-specific TFH cells. Specifically, mTORC2 functions to maintain TFH lineage specifications, including phenotypes, migratory characteristics, and functional properties. Thus, our results highlight the importance of mTORC2 in guarding TFH phenotypic and functional maturation.

11.
Sensors (Basel) ; 18(6)2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895805

RESUMO

Low concentration acetone gas detection is significantly important for diabetes diagnosis as 1.8⁻10 ppm of acetone exists in exhaled breath from diabetes patients. A new interlocking p+n field-effect transistor (FET) circuit has been proposed for Mn-doped ZnO nanoparticles (MZO) to detect the acetone gas at low concentration, especially close to 1.8 ppm. It is noteworthy that MZO in this interlocking amplification circuit shows a low voltage signal of <0.3 V to the acetone <2 ppm while it displays a transilient response with voltage signal >4.0 V to >2 ppm acetone. In other words, the response to acetone from 1 ppm to 2 ppm increases by ~1233%, which is competent to separate diabetic patients from healthy people. Moreover, the response to 2 ppm acetone is hardly influenced by high relative humidity of 85%. In the meanwhile, MZO in this interlocking circuit possesses a high acetone selectivity compared to formaldehyde, acetaldehyde, toluene and ethanol, suggesting a promising technology for the widespread qualitative screening of diabetes. Importantly, this interlocking circuit is also applicable to other types of metal oxide semiconductor gas sensors. The resistance jump of p- and n-FETs induced by the change of their gate voltages is deemed to make this interlocking circuit produce the transilient response.

12.
Sensors (Basel) ; 18(3)2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29509659

RESUMO

Nowadays, the detection of low concentration combustible methane gas has attracted great concern. In this paper, a coupling p+n field effect transistor (FET) amplification circuit is designed to detect methane gas. By optimizing the load resistance (RL), the response to methane of the commercial MP-4 sensor can be magnified ~15 times using this coupling circuit. At the same time, it decreases the limit of detection (LOD) from several hundred ppm to ~10 ppm methane, with the apparent response of 7.0 ± 0.2 and voltage signal of 1.1 ± 0.1 V. This is promising for the detection of trace concentrations of methane gas to avoid an accidental explosion because its lower explosion limit (LEL) is ~5%. The mechanism of this coupling circuit is that the n-type FET firstly generates an output voltage (VOUT) amplification process caused by the gate voltage-induced resistance change of the FET. Then, the p-type FET continues to amplify the signal based on the previous VOUT amplification process.

13.
Immunity ; 47(3): 538-551.e5, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930662

RESUMO

Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5'-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection.


Assuntos
Imunomodulação , Complexos Multiproteicos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Biomarcadores , Diferenciação Celular/imunologia , Análise por Conglomerados , Perfilação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Imunização , Imunofenotipagem , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/citologia , Serina-Treonina Quinases TOR/genética
14.
Sensors (Basel) ; 17(10)2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28953242

RESUMO

Pure In2O3 nanoparticles are prepared by a facile precipitation method and are further modified by Ag. The synthesized samples are characterized by scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, Raman and UV-Vis spectra. The results show the successful heterojunction formation between Ag and In2O3. Gas sensing property measurements show that the 5 mol % Ag-modified In2O3 sensor has the response of 67 to 50 ppm ethanol, and fast response and recovery time of 22.3 and 11.7 s. The response is over one magnitude higher than that of pure In2O3, which can be attributed to the enhanced catalytic activity of Ag-modified In2O3 as compared with the pure one. The mechanism of the gas sensor can be explained by the spillover effect of Ag, which enhances the oxygen adsorption onto the surface of In2O3 and thus give rise to the higher activity and larger surface barrier height.

15.
Sci Total Environ ; 609: 966-973, 2017 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-28783909

RESUMO

Landfills are so far the most common practice for the disposals of municipal solid waste (MSW) worldwide. Since MSW landfill receives miscellaneous wastes, including unused/expired antibiotics and bioactive wastes, it gradually becomes a huge potential bioreactor for breeding antibiotic resistance. Antibiotic resistance genes (ARGs) in landfill can flow to the environment through leakage of landfill leachate and pose a risk to public health. Using high throughput quantitative Polymerase Chain Reaction (HT-qPCR), we investigated the prevalence, diversity of ARGs and its association with various mobile genetic elements (MGEs) in MSW landfill groundwater. Totally 171 unique ARGs (belonging to 9 ARG types, encompassing 3 major resistance mechanisms) and 8 MGEs (6 transposase genes, and 2 integron-integrase genes) were identified. The normalized abundance of ARG was ranging from 0.24 to 5.66 copies/cell with multidrug, beta-lactams and tetracycline resistance genes being the most abundant ARG types. The co-occurrence pattern and significant correlation between MGEs and ARGs, indicated that MGEs may play an important role in the persistence and proliferation of ARGs. A Mantel test and Procrustes analysis suggested that ARG profiles were significantly correlated with bacterial community. Variation partitioning analysis (VPA) further demonstrated that bacterial community shifts contribute 65.8% of the total ARG variations. Additionally network analysis revealed that 15 bacterial taxa at family level might be the potential hosts of ARGs. These findings provide evidence that groundwater near MSW landfill is an underappreciated hotspot of antibiotic resistance and contribute to the spread of ARGs via the flowing contaminated groundwater.


Assuntos
Farmacorresistência Bacteriana , Genes Bacterianos , Água Subterrânea/microbiologia , Instalações de Eliminação de Resíduos , Antibacterianos , Humanos , Resíduos Sólidos , Tetraciclina
16.
AMB Express ; 7(1): 80, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28411348

RESUMO

Poultry are an important source of fecal contamination in environments. However, tools for detecting and tracking this fecal contamination are in the early stages of development. In practice, we have found that source tracking methods targeting the 16S rRNA genes of poultry-specific microbiota are not sufficiently sensitive. We therefore developed two quantitative PCR assays for detection of poultry fecal contamination, by targeting chicken and duck mitochondrial genes: NADH dehydrogenase subunit 5 (ND5) and cytochrome b (cytb). The sensitivity of both assays was 100% when tested on 50 chicken and duck fecal samples from 10 provinces of China. These assays were also tested in field samples, including soil and water collected adjacent to duck farms, and soils fertilized with chicken manure. Poultry mitochondrial DNA was detected in most of these samples, indicating that the assays are a robust method for monitoring environmental contamination with poultry feces. Complemented with existing indicators of fecal contamination, these markers should improve the efficiency and accuracy of microbial source tracking.

18.
Nature ; 537(7620): 412-428, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27501245

RESUMO

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Centro Germinativo/citologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Receptores CXCR5/metabolismo , Transferência Adotiva , Animais , Linfócitos B/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular , Doença Crônica , Feminino , Centro Germinativo/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Proteína 2 Inibidora de Diferenciação/metabolismo , Vírus da Coriomeningite Linfocítica/crescimento & desenvolvimento , Masculino , Camundongos , Receptores CXCR5/deficiência , Transdução de Sinais , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplante , Carga Viral/imunologia , Replicação Viral/imunologia
19.
Blood Adv ; 1(3): 219-230, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-29296937

RESUMO

As a key regulator of hippo signaling pathway, Mst kinases are emerging as one of the key signaling molecules that influence cell proliferation, organ size, cell migration, and cell polarity. In B lymphocytes, Mst1 deficiency causes the developmental defect of marginal zone (MZ) B cells, but how Mst1 regulates B-cell receptor (BCR) activation and differentiation remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we have demonstrated that Mst1 positively regulates BCR signaling via modulating CD19 transcriptional levels. Consistent with this, Mst1-deficient mice exhibited reduced BCR signaling, which is concurrent with defective BCR clustering and B-cell spreading on stimulatory lipid bilayers. The disruption of CD19-mediated Btk signaling by Mst1 deficiency leads to the severe defect in the differentiation of MZ and germinal center B cells. Mechanistic analysis showed that Mst1 upregulates the messenger RNA level of CD19 via regulating the transcriptional factor TEAD2 that directly binds to the consensus motif in the 3' untranslated region of cd19. Overall, our results reveal a new function of Mst1 in B cells and the mechanism by which Mst1 regulates the activation and differentiation of peripheral B cells.

20.
Nat Immunol ; 16(10): 1044-50, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26280998

RESUMO

The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Imunidade Inata , Linfócitos/citologia , Linfócitos/imunologia , Fator 1 de Transcrição de Linfócitos T/genética , Regulação para Cima , Animais , Células Cultivadas , Citometria de Fluxo , Camundongos , Análise em Microsséries , Fator 1 de Transcrição de Linfócitos T/metabolismo
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