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Pesquisa : E02.095.465.425.400.330.050 [Categoria DeCS]
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[PMID]:29360859
[Au] Autor:Zhou J; Bethune MT; Malkova N; Sutherland AM; Comin-Anduix B; Su Y; Baltimore D; Ribas A; Heath JR
[Ad] Endereço:NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, California, United States of America.
[Ti] Título:A kinetic investigation of interacting, stimulated T cells identifies conditions for rapid functional enhancement, minimal phenotype differentiation, and improved adoptive cell transfer tumor eradication.
[So] Source:PLoS One;13(1):e0191634, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differentiation, and response to stimulation hinders the co-optimization of these factors. We report on a biophysical investigation of how the short-term kinetics of T cell functional activation, through molecular stimulation and cell-cell interactions, competes with phenotype differentiation. T cells receive molecular stimulation for a few minutes to a few hours in bulk culture. Following this priming period, the cells are then analyzed at the transcriptional level, or isolated as single cells, with continuing molecular stimulation, within microchambers for analysis via 11-plex secreted protein assays. We resolve a rapid feedback mechanism, promoted by T cell-T cell contact interactions, which strongly amplifies T cell functional performance while yielding only minimal phenotype differentiation. When tested in mouse models of ACT, optimally primed T cells lead to complete tumor eradication. A similar kinetic process is identified in CD8+ and CD4+ T cells collected from a patient with metastatic melanoma.
[Mh] Termos MeSH primário: Transferência Adotiva
Imunofenotipagem
Neoplasias/terapia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Feminino
Citometria de Fluxo
Xenoenxertos
Seres Humanos
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180124
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191634


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[PMID]:29385359
[Au] Autor:Sarantopoulos S
[Ad] Endereço:From the Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke Cancer Institute, Duke University Medical Center, Durham, NC.
[Ti] Título:Allogeneic Stem-Cell Transplantation - A T-Cell Balancing ACT.
[So] Source:N Engl J Med;378(5):480-482, 2018 Feb 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Transplante de Células-Tronco Hematopoéticas
Interleucina-33/metabolismo
Subpopulações de Linfócitos T/imunologia
Imunologia de Transplantes
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Antígenos CD
Modelos Animais de Doenças
Interleucina-9/biossíntese
Camundongos
Transplante Homólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Interleukin-33); 0 (Interleukin-9)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMcibr1713238


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[PMID]:29223395
[Au] Autor:Takebe T; Sakamoto K; Higami Y; Harada Y
[Ad] Endereço:Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba,
[Ti] Título:A novel mouse model for tracking the fate of CXCR5-expressing T cells.
[So] Source:Biochem Biophys Res Commun;495(2):1642-1647, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The germinal center (GC) reaction, a critical process in the humoral immune response, requires follicular helper T (Tfh) cells. Tfh cells express the master transcription factor Bcl6 and chemokine receptor CXCR5, which enable them to migrate from the T cell zone to B cell follicles and interact with GC B cells. However, CXCR5 is downregulated when Tfh cells become memory cells. Therefore, it is difficult to track Tfh cells continuously in vivo. In this study, we generated a mouse strain, Cxcr5 R26 , in which the fluorescent protein tdTomato is inducibly expressed in CXCR5 cells by tamoxifen administration. After the oral administration of tamoxifen, most Tfh cells in Peyer's patches (PP) from Cxcr5 R26 mice were tdTomato . To track antigen-specific Tfh cells in vivo, OVA-specific OT-II T cells derived from Cxcr5 R26 mice were transferred to wild-type mice, and the recipient mice were immunized with OVA followed by tamoxifen administration. CXCR5 T cells became tdTomato and were mainly located in B cell follicles and GC areas 8 days after immunization. Four weeks after immunization, tdTomato OT-II T cells migrated from B cell follicles to the T-B border area and T cell zone after CXCR5 downregulation and CCR7 upregulation. These results indicate that Cxcr5 R26 mice are a useful tool for studying the cell fate of differentiated Tfh cells in vivo and therefore have implications for the development of therapeutic strategies for infectious and autoimmune diseases.
[Mh] Termos MeSH primário: Receptores CXCR5/metabolismo
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Linfócitos B/imunologia
Diferenciação Celular
Movimento Celular/imunologia
Centro Germinativo/citologia
Centro Germinativo/imunologia
Imunidade Humoral
Memória Imunológica
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Modelos Animais
Modelos Imunológicos
Ovalbumina/imunologia
Receptores CXCR5/genética
Linfócitos T Auxiliares-Indutores/citologia
Linfócitos T Auxiliares-Indutores/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blr1 protein, mouse); 0 (Receptors, CXCR5); 9006-59-1 (Ovalbumin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171211
[St] Status:MEDLINE


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[PMID]:29229383
[Au] Autor:Zhang X; Lv X; Song Y
[Ad] Endereço:School of Life Sciences, Zhengzhou University, Zhengzhou, China; Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. Electronic address: xuhuazhang@hotmail.com.
[Ti] Título:Short-term culture with IL-2 is beneficial for potent memory chimeric antigen receptor T cell production.
[So] Source:Biochem Biophys Res Commun;495(2):1833-1838, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Interleukin-2 (IL-2) has been extensively used to boost the body's immune cells, especially T cells. IL-2 is a cytokine that for many years was used to activate and amplify T cells. Due to its potent T cell growth-inducing functions in vitro, for many years, IL-2 was used for the culture and expansion of various T cell products, including tumor-infiltrating lymphocytes (TIL), T cell receptors T cells (TCR T), or genetically engineered cells with chimeric antigen receptors T cells (CAR T). Despite its positive effect on T cell production, the side-effect is not well studied. Here, we reported that long-term culture with IL-2 promotes terminal differentiation and impairs rather than boosts the function of chimeric antigen receptor T cells. However, short-term culture with IL-2 predominantly generates memory CAR T cell favorable for cancer treatment.
[Mh] Termos MeSH primário: Interleucina-2/farmacologia
Receptores de Antígenos de Linfócitos T/metabolismo
Subpopulações de Linfócitos T/efeitos dos fármacos
Subpopulações de Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Técnicas de Cultura de Células/métodos
Diferenciação Celular
Linhagem Celular Tumoral
Células Cultivadas
Seres Humanos
Memória Imunológica
Interleucina-2/imunologia
Camundongos
Neoplasias/imunologia
Neoplasias/terapia
Medicina de Precisão
Transdução de Sinais/imunologia
Subpopulações de Linfócitos T/citologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL2 protein, human); 0 (Interleukin-2); 0 (Receptors, Antigen, T-Cell)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE


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[PMID]:28455433
[Au] Autor:Nie Y; Sun L; Wu Y; Yang Y; Wang J; He H; Hu Y; Chang Y; Liang Q; Zhu J; Ye RD; Christman JW; Qian F
[Ad] Endereço:Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
[Ti] Título:AKT2 Regulates Pulmonary Inflammation and Fibrosis via Modulating Macrophage Activation.
[So] Source:J Immunol;198(11):4470-4480, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Idiopathic pulmonary fibrosis (IPF) is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although AKT2-mediated signaling pathways modulate inflammatory responses, their role in IPF has not been defined. We report that AKT2 deficiency ( ) protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to mice could restore pulmonary fibrosis. In response to IL-33 treatment, macrophages displayed decreased production of IL-13 and TGF-ß1 and attenuated phosphorylation of FoxO3a compared with macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of AKT2 and FoxO3a was remarkably upregulated. Collectively, these results indicate that AKT2 modulates pulmonary fibrosis through inducing TGF-ß1 and IL-13 production by macrophages, and inhibition of AKT2 may be a potential strategy for treating IPF.
[Mh] Termos MeSH primário: Ativação de Macrófagos
Pneumonia/imunologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Fibrose Pulmonar/imunologia
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Bleomicina/administração & dosagem
Bleomicina/efeitos adversos
Proteína Forkhead Box O3/genética
Proteína Forkhead Box O3/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Interleucina-13/administração & dosagem
Interleucina-13/genética
Interleucina-13/imunologia
Interleucina-33/imunologia
Interleucina-33/farmacologia
Macrófagos/imunologia
Camundongos
Proteínas Proto-Oncogênicas c-akt/deficiência
Proteínas Proto-Oncogênicas c-akt/genética
Fator de Crescimento Transformador beta1/genética
Fator de Crescimento Transformador beta1/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (FOXO3 protein, human); 0 (Forkhead Box Protein O3); 0 (FoxO3 protein, mouse); 0 (Il33 protein, mouse); 0 (Interleukin-13); 0 (Interleukin-33); 0 (Transforming Growth Factor beta1); 11056-06-7 (Bleomycin); EC 2.7.11.1 (AKT2 protein, human); EC 2.7.11.1 (Akt2 protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180127
[Lr] Data última revisão:
180127
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601503


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[PMID]:29272267
[Au] Autor:Peng Y
[Ad] Endereço:Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
[Ti] Título:Forced expression of IL-7R promotes CD8 T cell cytotoxicity to self antigen.
[So] Source:PLoS One;12(12):e0188112, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cross-presentation of apoptotic cell associated antigens by immature dendritic cells prevents the activation of self reactive CD8 T cells. Tolerized self reactive CD8 T cells down-regulate IL-7R expression on their surface. Whether over-expression of IL-7R can reverse their fate and function has not been examined. In this paper, we showed forced expression of IL-7R in OT-I T cells by a transgene enhanced CD8 T cell mediated diabetes in the RIP-mOVA model. Although IL-7R Tg (transgenic) did not completely reverse the deletion of OT-I T cells, it provided a significant survival advantage over w.t OT-I T cells. Furthermore, IL7R Tg OT-I T cells isolated from diabetic pancreata displayed increased production of IFN-γ, higher expression of T-bet, and increased externalization of CD107a. We also found that immature DCs containing apoptotic cells expressed high levels of PDL-1 on their surface. Although IL-7R Tg did not change PD1 expression on activated OT-I cells in vivo, the transgene enabled a significantly lower number of OT-I T cells to induce diabetes in the absence of PDL-1. Our results demonstrated that forced expression of IL-7R not only improved the functionality of tolerized CD8 T cells, it also acted in synergy with PDL-1 deficiency to further promote CD8 T cell cytotoxicity to self antigens.
[Mh] Termos MeSH primário: Autoantígenos/imunologia
Linfócitos T CD8-Positivos/imunologia
Receptores de Interleucina-7/metabolismo
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Apoptose
Anergia Clonal
Regulação para Baixo
Regulação da Expressão Gênica
Interferon gama/biossíntese
Camundongos
Camundongos Transgênicos
Ovalbumina/imunologia
Receptores de Interleucina-7/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Autoantigens); 0 (Receptors, Interleukin-7); 82115-62-6 (Interferon-gamma); 9006-59-1 (Ovalbumin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188112


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[PMID]:29262349
[Au] Autor:Fu B; Zhou Y; Ni X; Tong X; Xu X; Dong Z; Sun R; Tian Z; Wei H
[Ad] Endereço:Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei, Anhui 230001, China; Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Te
[Ti] Título:Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.
[So] Source:Immunity;47(6):1100-1113.e6, 2017 Dec 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a Eomes subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a Eomes NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.
[Mh] Termos MeSH primário: Aborto Habitual/imunologia
Transferência Adotiva
Proteínas de Transporte/secreção
Citocinas/secreção
Desenvolvimento Fetal/imunologia
Retardo do Crescimento Fetal/prevenção & controle
Peptídeos e Proteínas de Sinalização Intercelular/secreção
Células Matadoras Naturais/transplante
[Mh] Termos MeSH secundário: Aborto Habitual/genética
Aborto Habitual/patologia
Adulto
Animais
Antígenos CD/genética
Antígenos CD/imunologia
Fatores de Transcrição de Zíper de Leucina Básica/genética
Fatores de Transcrição de Zíper de Leucina Básica/imunologia
Proteínas de Transporte/genética
Proteínas de Transporte/imunologia
Microambiente Celular
Citocinas/genética
Citocinas/imunologia
Decídua/imunologia
Decídua/patologia
Feminino
Retardo do Crescimento Fetal/genética
Retardo do Crescimento Fetal/imunologia
Retardo do Crescimento Fetal/patologia
Feto
Regulação da Expressão Gênica no Desenvolvimento
Antígenos HLA-G/genética
Antígenos HLA-G/imunologia
Seres Humanos
Integrina alfa1/genética
Integrina alfa1/imunologia
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/imunologia
Células Matadoras Naturais/citologia
Células Matadoras Naturais/imunologia
Receptor B1 de Leucócitos Semelhante a Imunoglobulina/genética
Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Gravidez
Transdução de Sinais
Proteínas com Domínio T-Box/genética
Proteínas com Domínio T-Box/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Basic-Leucine Zipper Transcription Factors); 0 (Carrier Proteins); 0 (Cytokines); 0 (EOMES protein, human); 0 (HLA-G Antigens); 0 (Integrin alpha1); 0 (Intercellular Signaling Peptides and Proteins); 0 (LILRB1 protein, human); 0 (Leukocyte Immunoglobulin-like Receptor B1); 0 (NFIL3 protein, human); 0 (OGN protein, human); 0 (T-Box Domain Proteins); 0 (T-box transcription factor TBX21); 134034-50-7 (pleiotrophin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


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[PMID]:29216332
[Au] Autor:Kanatani S; Fuks JM; Olafsson EB; Westermark L; Chambers B; Varas-Godoy M; Uhlén P; Barragan A
[Ad] Endereço:Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
[Ti] Título:Voltage-dependent calcium channel signaling mediates GABAA receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii.
[So] Source:PLoS Pathog;13(12):e1006739, 2017 Dec.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection, γ-aminobutyric acid (GABA)/GABAA receptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAA receptors by GABA induces transient Ca2+ entry in DCs. Murine bone marrow-derived DCs preferentially expressed the L-type voltage-dependent Ca2+ channel (VDCC) subtype Cav1.3. Silencing of Cav1.3 by short hairpin RNA or selective pharmacological antagonism of VDCCs abolished the Toxoplasma-induced hypermigratory phenotype. In a mouse model of toxoplasmosis, VDCC inhibition of adoptively transferred Toxoplasma-infected DCs delayed the appearance of cell-associated parasites in the blood circulation and reduced parasite dissemination to target organs. The present data establish that T. gondii-induced hypermigration of DCs requires signaling via VDCCs and that Ca2+ acts as a second messenger to GABAergic signaling via the VDCC Cav1.3. The findings define a novel motility-related signaling axis in DCs and unveil that interneurons and DCs share common GABAergic motogenic pathways. T. gondii employs GABAergic non-canonical pathways to induce host cell migration and facilitate dissemination.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/imunologia
Sinalização do Cálcio
Células Dendríticas/imunologia
Receptores de GABA-A/imunologia
Toxoplasma/imunologia
Toxoplasmose/imunologia
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Movimento Celular
Células Cultivadas
Células Dendríticas/parasitologia
GABAérgicos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Toxoplasma/fisiologia
Toxoplasmose/parasitologia
Ácido gama-Aminobutírico/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cacna1d protein, mouse); 0 (Calcium Channels, L-Type); 0 (GABA Agents); 0 (Receptors, GABA-A); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006739


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[PMID]:28465528
[Au] Autor:Yu J; Chen L; Chen Y; Hasan MK; Ghia EM; Zhang L; Wu R; Rassenti LZ; Widhopf GF; Shen Z; Briggs SP; Kipps TJ
[Ad] Endereço:Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA.
[Ti] Título:Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells.
[So] Source:Leukemia;31(12):2608-2614, 2017 Dec.
[Is] ISSN:1476-5551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia (CLL) cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells by treatment with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via small interfering RNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2 and (3) induce activation of RhoA and Rac1 in CLL cells. Furthermore, CRISPR/Cas9 deletion of 14-3-3ζ in ROR1-negative CLL cell-line MEC1, and in MEC1 cells transfected to express ROR1 (MEC1-ROR1), demonstrated that 14-3-3ζ was necessary for the growth/engraftment advantage of MEC1-ROR1 over MEC1 cells. We identified a binding motif (RSPS SAS) in ROR1 for 14-3-3ζ. Site-directed mutagenesis of ROR1 demonstrated that serine-857 was required for the recruitment of 14-3-3ζ and ARHGEF2 to ROR1, and activation of RhoA and Rac1. Collectively, this study reveals that 14-3-3ζ plays a critical role in Wnt5a/ROR1 signaling, leading to enhanced CLL migration and proliferation.
[Mh] Termos MeSH primário: Proteínas 14-3-3/metabolismo
Quimiotaxia/imunologia
Leucemia Linfocítica Crônica de Células B/etiologia
Leucemia Linfocítica Crônica de Células B/metabolismo
Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo
Proteína Wnt-5a/metabolismo
[Mh] Termos MeSH secundário: Transferência Adotiva
Motivos de Aminoácidos
Animais
Sítios de Ligação
Proliferação Celular
Células Cultivadas
Modelos Animais de Doenças
Progressão da Doença
Seres Humanos
Leucemia Linfocítica Crônica de Células B/patologia
Camundongos
Camundongos Knockout
Ligação Proteica
Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (ARHGEF2 protein, human); 0 (Rho Guanine Nucleotide Exchange Factors); 0 (WNT5A protein, human); 0 (Wnt-5a Protein); EC 2.7.10.1 (ROR1 protein, human); EC 2.7.10.1 (Receptor Tyrosine Kinase-like Orphan Receptors)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1038/leu.2017.132


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[PMID]:28747319
[Au] Autor:Sudworth A; Vaage JT; Inngjerdingen M; Kveberg L
[Ad] Endereço:Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
[Ti] Título:Frontline Science: A hyporesponsive subset of rat NK cells negative for Ly49s3 and NKR-P1B are precursors to the functionally mature NKR-P1B subset.
[So] Source:J Leukoc Biol;102(6):1289-1298, 2017 Dec.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rat NK cells are divided into major subsets expressing either Ly49 receptors or the inhibitory NKR-P1B receptor in conjunction with NKG2A/C/E receptors. A minor subset of NKp46 cells lacking expression of both Ly49 receptors and NKR-P1B is present in blood and spleen and is associated with decreased functional competence. We hypothesized that this subset may represent precursors to Ly49 and/or NKR-P1B NK cells. When cultured in vitro in IL-2 and IL-15 or adoptively transferred to syngeneic hosts, a portion of NKR-P1B Ly49s3 cells transformed to express NKR-P1B, but very little Ly49s3. Acquisition of NKR-P1B by NKR-P1B Ly49s3 cells coincided with increased degranulation. In addition, although NKR-P1B Ly49s3 cells highly proliferate, proliferative activity was reduced upon acquisition of NKR-P1B at comparable levels to bona fide NKR-P1B NK cells. A fraction of NKR-P1B Ly49s3 cells remained negative for NKR-P1B, both in vitro and after adoptive transfer in vivo. Most NKR-P1B Ly49s3 cells expressed the transcription factor Eomesodermin and NK cell markers, indicating that these cells represent conventional NK cells. Our findings suggest that the NKR-P1B Ly49s3 NK cells are precursors to NKR-P1B single-positive cells and that functional competence is acquired upon expression of NKR-P1B.
[Mh] Termos MeSH primário: Diferenciação Celular
Células Matadoras Naturais/citologia
Células Matadoras Naturais/metabolismo
Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo
Receptores Imunológicos/metabolismo
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Antígeno CD11b/metabolismo
Degranulação Celular/efeitos dos fármacos
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Interleucina-15/farmacologia
Interleucina-2/farmacologia
Células Matadoras Naturais/efeitos dos fármacos
Células Matadoras Naturais/fisiologia
Fenótipo
Ratos
Baço/citologia
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD11b Antigen); 0 (Interleukin-15); 0 (Interleukin-2); 0 (Ly49s3 protein, rat); 0 (NK Cell Lectin-Like Receptor Subfamily A); 0 (NKR-P1B protein, rat); 0 (Receptors, Immunologic)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.1HI0517-177RR



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