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1.
J Mass Spectrom ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31524312

RESUMO

Cytidine 5'-triphosphate synthetase (CTPS) is known to be a central enzyme in the de novo synthesis of CTP. We have recently demonstrated that a deficiency in CTPS1 is associated with an impaired capacity of activated lymphocytes to proliferate leading to a combined immunodeficiency disease. In order to better document its role in immunomodulation, we developed a method for measuring CTPS activity in human lymphocytes. Using liquid chromatography-mass spectrometry, we quantified CTPS activity by measuring CTP in cell lysates. A stable isotope analog of CTP served as internal standard. We characterized the kinetic parameters Vmax and Km of CTPS and verified that an inhibition of the enzyme activity was induced after 3-deazauridine (3DAU) treatment, a known inhibitor of CTPS. We then determined CTPS activity in healthy volunteers, in a family whose child displayed a homozygous mutation in CTPS1 gene and in patients who had developed or not a chronic lung allograft dysfunction (CLAD) after lung transplantation. Linearity of the CTP determination was observed up to 451 µmol/L, with accuracy in the 15% tolerance range. Michaelis-Menten kinetics for lysates of resting cells were Km =280±310 µmol/L for UTP, Vmax =83±20 pmol/min, and for lysates of activated PBMCs, Km =230±280 µmol/L for UTP, Vmax =379±90 pmol/min. Treatment by 3DAU and homozygous mutation in CTPS1 gene abolished the induction of CTPS activity associated with cell stimulation, and CTPS activity was significantly reduced in the patients who developed CLAD. We conclude that this test is suitable to reveal the involvement of CTPS alteration in immunodeficiency.

2.
J Exp Med ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537641

RESUMO

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand-expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137-CD137L pathway, highlighting its critical role in immunity to EBV.

3.
Immunol Rev ; 291(1): 174-189, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402499

RESUMO

Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV - notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T- and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions.

4.
Hematol Oncol ; 37(4): 483-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.


Assuntos
Eritema Infeccioso/complicações , Doença de Hodgkin/etiologia , Linfoma de Células B/etiologia , Neoplasias Primárias Múltiplas/etiologia , Viremia/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Medula Óssea/patologia , Medula Óssea/virologia , Criança , Eritema Infeccioso/sangue , Eritema Infeccioso/patologia , Eritema Infeccioso/virologia , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Neoplasias Primárias Múltiplas/patologia , Pancitopenia/etiologia , Pseudolinfoma/etiologia , Indução de Remissão , Rituximab/administração & dosagem , Linfócitos T/patologia , Sequenciamento Completo do Exoma
7.
Eur J Immunol ; 49(6): 894-910, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30912587

RESUMO

It is established that iNKT cells are a cell type that require strong TCR signal for their proper development and represent a model for thymic agonist selection. The nature of the signal perceived by iNKT cells promoting their specification is not well understood. To address this question, we analyzed iNKT cell development in relevant TCR Vα14-Jα18 alpha chain transgenic mice (Vα14Tg). In CD4-Vα14Tg mice, where the transgene is driven by CD4 promoter, we identified a block in iNKT cell development at early developmental stages due to a reduced expression of key transcription factors accompanied with a reduced TCR expression levels. This indicates that TCR signal strength control iNKT cell differentiation. Importantly, we found in WT mice that early precursors of iNKT cells express higher TCR levels compared to positively selected precursors of mainstream T cells showing that TCR levels could contribute to the strength of iNKT cell TCR signaling. Overall, our study highlights TCR signal strength associated with a higher TCR density as an important regulator of iNKT cell lineage specification.

8.
Genes Chromosomes Cancer ; 58(8): 595-601, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30779244

RESUMO

Burkitt lymphoma (BL) is characterized by a translocation of the MYC oncogene that leads to the upregulation of MYC expression, cell growth and proliferation. It is well-established that MYC translocation is not a sufficient genetic event to cause BL. Next-generation sequencing has recently provided a comprehensive analysis of the landscape of additional genetic events that contribute to BL lymphomagenesis. Refractory BL or relapsing BL are almost always incurable as a result of the selection of a highly chemoresistant clonally related cell population. Conversely, a few BL recurrence cases arising from clonally distinct tumors have been reported and were associated with a favorable outcome similar to that reported for first-line treatment. Here, we used an unusual case of recurrent but clonally distinct EBV+ BL to highlight the key genetic events that drive BL lymphomagenesis. By whole exome sequencing, we established that ID3 gene was targeted by distinct mutations in the two clonally unrelated diseases, highlighting the crucial role of this gene during lymphomagenesis. We also detected a heterozygous E1021K PIK3CD mutation, thus increasing the spectrum of somatic mutations altering the PI3K signaling pathway in BL. Interestingly, this mutation is known to be associated with activated phosphoinositide 3-kinase delta syndrome (APDS). Finally, we also identified an inherited heterozygous truncating c.5791CT FANCM mutation that may contribute to the unusual recurrence of BL.

10.
Front Immunol ; 9: 1103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942301

RESUMO

Epstein-Barr Virus (EBV) is a gamma-herpes virus that infects 90% of humans without any symptoms in most cases, but has an oncogenic potential, especially in immunocompromised individuals. In the past 30 years, several primary immunodeficiencies (PIDs) associated with a high risk to develop EBV-associated lymphoproliferative disorders (LPDs), essentially consisting of virus-associated hemophagocytic syndrome, non-malignant and malignant B-cell LPDs including non-Hodgkin and Hodgkin's types of B lymphomas have been characterized. Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. Penetrance of EBV infection ranges from 50 to 100% in those PIDs. Description of large cohorts and case reports has refined the specific phenotypes associated with these PIDs helping to the diagnosis. Specific pathways required for protective immunity to EBV have emerged from studies of these PIDs. SLAM-associated protein-dependent SLAM receptors and MAGT1-dependent NKG2D pathways are important for T and NK-cell cytotoxicity toward EBV-infected B-cells, while CD27-CD70 interactions are critical to drive the expansion of EBV-specific T-cells. CTPS1 and RASGRP1 deficiencies further strengthen that T-lymphocyte expansion is a key step in the immune response to EBV. These pathways appear to be also important for the anti-tumoral immune surveillance of abnormal B cells. Monogenic PIDs should be thus considered in case of any EBV-associated LPDs.

11.
J Clin Invest ; 128(7): 3071-3087, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889099

RESUMO

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

13.
Int J Hematol ; 108(3): 319-328, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29777376

RESUMO

Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD were used in this comprehensive molecular diagnosis. Causative gene mutations (involving PRF1 and SH2D1A) were detected in two of the 19 patients studied. This comprehensive diagnosis method effectively detected mutations in all coding exons of 23 genes with sufficient read numbers for each amplicon. This comprehensive molecular diagnostic method using PCR and NGS provides a rapid, accurate, low-cost diagnosis for patients with XLP or XLP-like diseases.


Assuntos
Análise Mutacional de DNA/métodos , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Perforina/genética , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Adulto Jovem
14.
J Crohns Colitis ; 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29788237

RESUMO

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment. Methods: 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally. Results: Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitis and perianal lesions and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations previously missed by WES. Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

15.
EMBO Mol Med ; 10(2): 188-199, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29282224

RESUMO

Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.

16.
J Allergy Clin Immunol ; 142(2): 595-604.e16, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29155103

RESUMO

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically. OBJECTIVE: We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype. METHODS: Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported. RESULTS: The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells. CONCLUSIONS: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause.

17.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
18.
J Exp Med ; 214(1): 73-89, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011863

RESUMO

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin's lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.


Assuntos
Ligante CD27/fisiologia , Infecções por Vírus Epstein-Barr/imunologia , Transdução de Sinais/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Linfócitos B/imunologia , Ligante CD27/deficiência , Ligante CD27/genética , Criança , Códon sem Sentido , Humanos , Ativação Linfocitária , Masculino , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia
19.
Eur J Immunol ; 46(9): 2162-74, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27338553

RESUMO

Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.


Assuntos
Diferenciação Celular/imunologia , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biomarcadores , Células Cultivadas , Imunofenotipagem , Interleucina-17/biossíntese , Interleucina-4/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/deficiência , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética
20.
Nat Immunol ; 17(4): 387-96, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26878112

RESUMO

Activation of natural killer (NK) cells by hematopoietic target cells is controlled by the SLAM family of receptors and by the associated SAP family of adaptors. Here we found that SLAM receptors also enhanced NK cell activation by nonhematopoietic target cells, which lack ligands for SLAM receptors. This function was mediated by SLAMF6, a homotypic SLAM receptor found on NK cells and other hematopoietic cells, and was regulated by SAP adaptors, which uncoupled SLAM receptors from phosphatase SHP-1 and diminished the effect of SLAMF6 on NK cell responsiveness toward nonhematopoietic cells. Thus, in addition to their role in NK cell activation by hematopoietic cells, the SLAM-SAP pathways influence responsiveness toward nonhematopoietic targets by a process akin to NK cell 'education'.


Assuntos
Antígenos CD/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Matadoras Naturais/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Receptores de Superfície Celular/imunologia , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Células HeLa , Humanos , Imunidade Inata , Ativação Linfocitária , Melanoma Experimental , Camundongos , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Família de Moléculas de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária
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