RESUMO
mRNA translation and decay are tightly interconnected processes both in the context of mRNA quality-control pathways and for the degradation of functional mRNAs. Cotranslational mRNA degradation through codon usage, ribosome collisions, and the recruitment of specific proteins to ribosomes is an important determinant of mRNA turnover. However, the extent to which translation-dependent mRNA decay (TDD) and translation-independent mRNA decay (TID) pathways participate in the degradation of mRNAs has not been studied yet. Here we describe a comprehensive analysis of basal and signal-induced TDD and TID in mouse primary CD4+ T cells. Our results indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner. Our analysis further identifies the length of untranslated regions, the density of ribosomes, and GC3 content as important determinants of TDD magnitude. Consistently, all transcripts that undergo changes in ribosome density within their coding sequence upon T cell activation display a corresponding change in their TDD level. Moreover, we reveal a dynamic modulation in the relationship between GC3 content and TDD upon T cell activation, with a reversal in the impact of GC3- and AU3-rich codons. Altogether, our data show a strong and dynamic interconnection between mRNA translation and decay in mammalian primary cells.
Assuntos
Ativação Linfocitária , Biossíntese de Proteínas , Estabilidade de RNA , RNA Mensageiro , Ribossomos , Ribossomos/metabolismo , Animais , Camundongos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Linfócitos T CD4-Positivos/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T/metabolismoRESUMO
The subclassification of immunology into innate and adaptive immunity is challenged by innate-like T lymphocytes that use innate receptors to respond rapidly to stress despite expressing T cell antigen receptors (TCRs), a hallmark of adaptive immunity. In studies that explain how such cells can straddle innate and adaptive immunity, we found that signaling via antigen receptors, whose conventional role is to facilitate clonal T cell activation, was critical for the development of innate-like T cells but then was rapidly attenuated, which accommodated the cells' innate responsiveness. These findings permitted the identification of a previously unknown innate-like T cell subset and indicate that T cell hyporesponsiveness, a state traditionally linked to tolerance, may be fundamental to T cells entering the innate compartment and thereby providing lymphoid stress surveillance.
Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteína-Tirosina Quinase ZAP-70/imunologia , Proteína-Tirosina Quinase ZAP-70/metabolismoRESUMO
The role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration. This inhibition was also more pronounced for CD4 T cells than for CD8 T cell subsets, and was dependent on S1PR2, as shown using the S1PR2 antagonist JTE-013. S1PR1 was progressively downregulated during T cell differentiation whereas S1PR2 expression remained stable. Our results suggest that the ratio between S1PR1 and S1PR2 governs the migratory behavior of T cell subsets. They also challenge previous models of the role of S1P in lymphocyte recirculation and suggest that S1P promotes retention of memory T cell subsets in secondary lymphoid organs, via S1PR2.
Assuntos
Quimiotaxia de Leucócito/imunologia , Memória Imunológica , Lisofosfolipídeos/imunologia , Esfingosina/análogos & derivados , Linfócitos T/imunologia , Quimiocinas/metabolismo , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Tecido Linfoide/imunologia , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/imunologia , Receptores de Esfingosina-1-Fosfato , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismoRESUMO
γδ T cells are major providers of the pro-inflammatory cytokines interferon-γ (IFNγ) and interleukin-17 (IL-17) in protective or pathogenic immune responses. Notably, murine γδ T cells commit to either IFNγ or IL-17 production during development in the thymus, before any subsequent activation in the periphery. Here we discuss the molecular networks that underlie thymic γδ T cell differentiation, as well as the mechanisms that sustain or modify their functional properties in the periphery. We concentrate on recent findings on lymphoid and tissue-resident γδ T cell subpopulations, with an emphasis on genome-wide studies and their added value to elucidate the regulation of γδ T cell differentiation at the transcriptional and epigenetic (chromatin) levels.
Assuntos
Diferenciação Celular , Epigênese Genética , Linfócitos T/citologia , Linfócitos T/imunologia , Transcrição Gênica , Animais , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Timo/citologiaRESUMO
CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.
Assuntos
Neoplasias , Viroses , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Neoplasias/metabolismo , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Viroses/metabolismoRESUMO
Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that Tax(HTLV-1) interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αß T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a "Human Immune System" (HIS) Rag2â»/â»Î³(c)â»/â» mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2â»/â»Î³câ»/â» mice, mature single-positive (SP) CD4⺠and CD8⺠cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2â»/â»Î³(c)â»/â» animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1.
Assuntos
Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Timócitos/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Infecções por HTLV-I/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia-Linfoma de Células T do Adulto/etiologia , Camundongos , Timócitos/virologia , Quimeras de Transplante/imunologia , Transplante Heterólogo , Carga ViralRESUMO
The RGS1 gene is associated with celiac disease, multiple sclerosis, and type I diabetes, which are all T cell-mediated pathologies, yet there is no reported analysis of regulator of G protein signaling (RGS)1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS1 depletion selectively enhances such chemotaxis in gut T cells and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease.
Assuntos
Movimento Celular , Quimiotaxia de Leucócito/imunologia , Colite/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Proteínas RGS/imunologia , Linfócitos T/imunologia , Animais , Separação Celular , Colite/metabolismo , Citometria de Fluxo , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Proteínas RGS/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/metabolismo , TransfecçãoRESUMO
T cell receptor (TCR) Vγ4-expressing γδ T cells comprise interferon γ (IFNγ)- and interleukin-17 (IL-17)-producing effector subsets, with a preference for IL-17 effector fate decisions during early ontogeny. The existence of adult-thymus-derived IL-17+ T cells (γδ17) remains controversial. Here, we use a mouse model in which T cells are generated exclusively in the adult thymus and employ single-cell chromatin state analysis to study their development. We identify adult-thymus-derived Vγ4 T cells that have all the molecular programs to become IL-17 producers. However, they have reduced IL-17 production capabilities and rarely reach the periphery. Moreover, this study provides high-resolution profiles of Vγ4 T cells in the adult thymus and lymph nodes and identifies Zeb1 as a potential γδ17 cell regulator. Together, this study provides valuable insights into the developmental traits of Vγ4 T cells during adulthood and supports the idea of age-specific signals required for thymic export and/or peripheral maturation of γδ17 cells.
Assuntos
Interleucina-17 , Receptores de Antígenos de Linfócitos T gama-delta , Camundongos , Animais , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Camundongos Endogâmicos C57BL , Linfócitos T , Timo , Subpopulações de Linfócitos T , Proteínas Proto-Oncogênicas c-mafRESUMO
γδ T lymphocytes are commonly viewed as embracing properties of both adaptive and innate immunity. Contributing to this is their responsiveness to pathogen products, either with or without the involvement of the TCR and its coreceptors. This study clarifies this paradoxical behavior by showing that these two modes of responsiveness are the properties of two discrete sets of murine lymphoid γδ T cells. Thus, MyD88 deficiency severely impaired the response to malaria infection of CD27((-)), IL-17A-producing γδ T cells, but not of IFN-γ-producing γδ cells. Instead, the latter compartment was severely contracted by ablating CD27, which synergizes with TCRγδ in the induction of antiapoptotic mediators and cell cycle-promoting genes in CD27((+)), IFN-γ-secreting γδ T cells. Hence, innate versus adaptive receptors differentially control the peripheral pool sizes of discrete proinflammatory γδ T cell subsets during immune responses to infection.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon gama/biossíntese , Interleucina-17/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa/genética , Animais , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Imunidade Inata/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/deficiência , Rhadinovirus/imunologia , Transdução de Sinais/genética , Subpopulações de Linfócitos T/parasitologia , Subpopulações de Linfócitos T/virologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologiaRESUMO
CRISPR knockout (KO) screens have identified host factors regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Here, we conducted a meta-analysis of these screens, which showed a high level of cell-type specificity of the identified hits, highlighting the necessity of additional models to uncover the full landscape of host factors. Thus, we performed genome-wide KO and activation screens in Calu-3 lung cells and KO screens in Caco-2 colorectal cells, followed by secondary screens in four human cell lines. This revealed host-dependency factors, including AP1G1 adaptin and ATP8B1 flippase, as well as inhibitors, including mucins. Interestingly, some of the identified genes also modulate Middle East respiratory syndrome coronavirus (MERS-CoV) and seasonal human coronavirus (HCoV) (HCoV-NL63 and HCoV-229E) replication. Moreover, most genes had an impact on viral entry, with AP1G1 likely regulating TMPRSS2 activity at the plasma membrane. These results demonstrate the value of multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential targets for therapeutic interventions.
Assuntos
COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , COVID-19/genética , Células CACO-2 , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , SARS-CoV-2/genética , Estações do AnoRESUMO
Innate immunity is the frontline of defense against infections and tissue damage. It is a fast and semi-specific response involving a myriad of processes essential for protecting the organism. These reactions promote the clearance of danger by activating, among others, an inflammatory response, the complement cascade and by recruiting the adaptive immunity. Any disequilibrium in this functional balance can lead to either inflammation-mediated tissue damage or defense inefficiency. A dynamic and coordinated gene expression program lies at the heart of the innate immune response. This expression program varies depending on the cell-type and the specific danger signal encountered by the cell and involves multiple layers of regulation. While these are achieved mainly via transcriptional control of gene expression, numerous post-transcriptional regulatory pathways involving RNA-binding proteins (RBPs) and other effectors play a critical role in its fine-tuning. Alternative splicing, translational control and mRNA stability have been shown to be tightly regulated during the innate immune response and participate in modulating gene expression in a global or gene specific manner. More recently, microRNAs assisting RBPs and post-transcriptional modification of RNA bases are also emerging as essential players of the innate immune process. In this review, we highlight the numerous roles played by specific RNA-binding effectors in mediating post-transcriptional control of gene expression to shape innate immunity.
Assuntos
Regulação da Expressão Gênica , Imunidade Inata , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo , Animais , Biomarcadores , Suscetibilidade a Doenças , Epigênese Genética , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Biossíntese de Proteínas , Estabilidade de RNA , Transdução de SinaisRESUMO
The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.
Assuntos
Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , Aves , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Influenza Aviária/imunologia , Influenza Aviária/virologia , Influenza Humana/imunologia , Influenza Humana/virologia , Aves Domésticas , Replicação ViralRESUMO
T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4-CD8- double-negative (DN) stage 2 (DN2). Zeb1 expression was further increased in the CD4+CD8+ double-positive (DP) stage before decreasing in more mature T cell subsets. We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb1 hypomorphic mutations. The Zeb1 mutation profoundly affected all thymic subsets, especially DN2 and DP cells. Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner. In the periphery of Cellophane mice, the number of conventional T cells was near normal, but invariant NKT cells, NK1.1+ γδ T cells and Ly49+ CD8 T cells were virtually absent. This suggested that Zeb1 regulates the development of unconventional T cell types from DP progenitors. A transcriptomic analysis of WT and Cellophane DP cells revealed that Zeb1 regulated the expression of multiple genes involved in the cell cycle and TCR signaling, which possibly occurred in cooperation with Tcf1 and Heb. Indeed, Cellophane DP cells displayed stronger signaling than WT DP cells upon TCR engagement in terms of the calcium response, phosphorylation events, and expression of early genes. Thus, Zeb1 is a key regulator of the cell cycle and TCR signaling during thymic T cell development. We propose that thymocyte selection is perturbed in Zeb1-mutated mice in a way that does not allow the survival of unconventional T cell subsets.
Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta , Subpopulações de Linfócitos T , Animais , Diferenciação Celular , Proliferação de Células , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transdução de Sinais/genética , TimoRESUMO
Several genome-wide CRISPR knockout screens have been conducted to identify host factors regulating SARS-CoV-2 replication, but the models used have often relied on overexpression of ACE2 receptor. Additionally, such screens have yet to identify the protease TMPRSS2, known to be important for viral entry at the plasma membrane. Here, we conducted a meta-analysis of these screens and showed a high level of cell-type specificity of the identified hits, arguing for the necessity of additional models to uncover the full landscape of SARS-CoV-2 host factors. We performed genome-wide knockout and activation CRISPR screens in Calu-3 lung epithelial cells, as well as knockout screens in Caco-2 intestinal cells. In addition to identifying ACE2 and TMPRSS2 as top hits, our study reveals a series of so far unidentified and critical host-dependency factors, including the Adaptins AP1G1 and AP1B1 and the flippase ATP8B1. Moreover, new anti-SARS-CoV-2 proteins with potent activity, including several membrane-associated Mucins, IL6R, and CD44 were identified. We further observed that these genes mostly acted at the critical step of viral entry, with the notable exception of ATP8B1, the knockout of which prevented late stages of viral replication. Exploring the pro- and anti-viral breadth of these genes using highly pathogenic MERS-CoV, seasonal HCoV-NL63 and -229E and influenza A orthomyxovirus, we reveal that some genes such as AP1G1 and ATP8B1 are general coronavirus cofactors. In contrast, Mucins recapitulated their known role as a general antiviral defense mechanism. These results demonstrate the value of considering multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential new targets for therapeutic interventions.
RESUMO
Several genome-wide CRISPR knockout screens have been conducted to identify host factors regulating SARS-CoV-2 replication, but the models used have often relied on overexpression of ACE2 receptor. Additionally, such screens have yet to identify the protease TMPRSS2, known to be important for viral entry at the plasma membrane. Here, we conducted a meta-analysis of these screens and showed a high level of cell-type specificity of the identified hits, arguing for the necessity of additional models to uncover the full landscape of SARS-CoV-2 host factors. We performed genome-wide knockout and activation CRISPR screens in Calu-3 lung epithelial cells, as well as knockout screens in Caco-2 intestinal cells. In addition to identifying ACE2 and TMPRSS2 as top hits, our study reveals a series of so far unidentified and critical host-dependency factors, including the Adaptins AP1G1 and AP1B1 and the flippase ATP8B1. Moreover, new anti-SARS-CoV-2 proteins with potent activity, including several membrane-associated Mucins, IL6R, and CD44 were identified. We further observed that these genes mostly acted at the critical step of viral entry, with the notable exception of ATP8B1, the knockout of which prevented late stages of viral replication. Exploring the pro- and anti-viral breadth of these genes using highly pathogenic MERS-CoV, seasonal HCoV-NL63 and -229E and influenza A orthomyxovirus, we reveal that some genes such as AP1G1 and ATP8B1 are general coronavirus cofactors. In contrast, Mucins recapitulated their known role as a general antiviral defense mechanism. These results demonstrate the value of considering multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential new targets for therapeutic interventions.
RESUMO
The human T-cell leukemia virus type 1 (HTLV-1) Tax transactivator is known to induce or repress various cellular genes, several of them encoding transcription factors. As Tax is known to deregulate various basic bHLH factors, we looked more specifically at its effect on TAL1 (T-cell acute lymphoblastic leukemia 1), also known as SCL (stem cell leukemia). Indeed, TAL1 is deregulated in a high percentage of T-cell acute lymphoblastic leukemia cells, and its oncogenic properties are well-established. Here we show that Tax induces transcription of this proto-oncogene by stimulating the activity of the TAL1 gene promoter 1b, through both the CREB and NF-kappaB pathways. It was also observed that TAL1 upregulates HTLV-1 promoter activity, in either the presence or the absence of Tax. The viral promoter is inhibited in trans by expression of the E2A protein E47, and TAL1 is able to abrogate this inhibition. These data show the existence of a positive feedback loop between Tax and TAL1 expression and support the notion that this proto-oncogene participates in generation of adult T-cell leukemia/lymphoma by increasing the amount of the Tax oncoprotein but also possibly by its own transforming activities.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Viral da Expressão Gênica , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Leucemia-Linfoma de Células T do Adulto/virologia , Proteínas Proto-Oncogênicas/metabolismo , Sítios de Ligação , Linhagem Celular , Retroalimentação Fisiológica , Células HeLa , Humanos , Modelos Biológicos , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Timo/citologiaAssuntos
DNA Viral/genética , Inflamassomos/farmacologia , Neoplasias Experimentais , Papillomaviridae/genética , Proteínas E7 de Papillomavirus/genética , Neoplasias Cutâneas/genética , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese , Camundongos , Camundongos Transgênicos , Proteínas E7 de Papillomavirus/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Perfilação da Expressão Gênica , Memória Imunológica/genética , Baço/citologia , Animais , Linfócitos T CD8-Positivos/virologia , Quimiocinas/genética , Quimiocinas/metabolismo , Regulação da Expressão Gênica , Homeostase , Humanos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Família Multigênica , Orthomyxoviridae/fisiologia , Peptídeos/imunologia , Fenótipo , Análise de Componente Principal , Especificidade da EspécieRESUMO
The regulatory Tax protein of HTLV-1 (Human T-cell Leukaemia Virus type 1) is critically involved in the initiation of ATL (adult T-cell leukaemia). Indeed, Tax provides infected T-cells with a growth advantage and with the potential to get transformed through the deregulation of cell-cycle progression and the acquisition of genetic alterations. Considering that leukemias are induced by disturbances in hematopoietic cells development, we hypothesize that the expression of Tax in human immature thymocytes is a prerequisite to the emergence of ATL cells. Studies of alph abeta T-cell development in the thymus have shown that beta-selection, an early important checkpoint, is regulated by transcription factors that are decisive in the control of cell proliferation, differentiation and survival. Interestingly, Tax is endowed with the ability to interfere with the activity of these transcription factors. We therefore propose that the HTLV-1 infection of these specific target thymocytes leads to a transcriptional deregulation of early alphabeta T cell development, thus inducing a pre-leukemogenic event that favours the subsequent proliferation of ATL cells.
Assuntos
Transformação Celular Neoplásica , Produtos do Gene tax/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Linfócitos T/citologia , HumanosRESUMO
The human pre-T-cell receptor alpha (TCRalpha; pTalpha) gene encodes a polypeptide which associates with the TCRbeta chain and CD3 molecules to form the pre-TCR complex. The surface expression of the pre-TCR is pTalpha dependent, and signaling through this complex triggers an early alphabeta T-cell developmental checkpoint inside the thymus, known as beta-selection. E2A transcription factors, which are involved at multiple stages of T-cell development, regulate the transcription of the pTalpha gene. Here we show that the regulatory protein Tax of the human T-cell leukemia virus type 1 (HTLV-1) efficiently suppresses the E47-mediated activation of the pTalpha promoter. Furthermore, we report that in Tax lentivirally transduced human MOLT-4 T cells, which constitutively express the pTalpha gene, the amount of pTalpha transcripts decreases. Such a decrease is not observed in MOLT-4 cells transduced by a vector encoding the Tax mutant K88A, which is unable to interact with p300. These data underline that Tax inhibits pTalpha transcription by recruiting this coactivator. Finally, we show that the expression of Tax in human immature thymocytes results in a decrease of pTalpha gene transcription but does not modify the level of E47 transcripts. These observations indicate that Tax, by silencing E proteins, down-regulates pTalpha gene transcription during early thymocyte development. They further provide evidence that Tax can interfere with an important checkpoint during T-cell differentiation in the thymus.