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1.
Annu Rev Immunol ; 42(1): 427-53, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38360547

RESUMO

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.


Assuntos
Proteína AIRE , Autoimunidade , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Animais , Timo/imunologia , Timo/metabolismo , Mutação , Tolerância Imunológica , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo
2.
Annu Rev Immunol ; 36: 549-578, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29677469

RESUMO

Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation. In resting lymphocytes, TEC kinases are autoinhibited, and multiple interactions between the regulatory and kinase domains maintain low activity. Following TCR stimulation, newly generated signaling modules compete with the autoinhibited core and shift the conformational ensemble to the fully active kinase. This multidomain control over kinase activation state provides a structural mechanism to account for ITK's ability to tune the TCR signal.


Assuntos
Ativação Linfocitária , Proteínas Tirosina Quinases/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Humanos , Ativação Linfocitária/imunologia , Fosfolipase C gama/metabolismo , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Tirosina Quinases/química , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo
3.
Cell ; 187(11): 2785-2800.e16, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657604

RESUMO

Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired "synpoptosis" circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.


Assuntos
Morte Celular , Humanos , Apoptose , Caspases/metabolismo , Células HEK293 , Proteólise , Piroptose/efeitos dos fármacos , Biologia Sintética/métodos , Células Cultivadas
4.
Cell ; 186(17): 3642-3658.e32, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37437570

RESUMO

A system for programmable export of RNA molecules from living cells would enable both non-destructive monitoring of cell dynamics and engineering of cells capable of delivering executable RNA programs to other cells. We developed genetically encoded cellular RNA exporters, inspired by viruses, that efficiently package and secrete cargo RNA molecules from mammalian cells within protective nanoparticles. Exporting and sequencing RNA barcodes enabled non-destructive monitoring of cell population dynamics with clonal resolution. Further, by incorporating fusogens into the nanoparticles, we demonstrated the delivery, expression, and functional activity of exported mRNA in recipient cells. We term these systems COURIER (controlled output and uptake of RNA for interrogation, expression, and regulation). COURIER enables measurement of cell dynamics and establishes a foundation for hybrid cell and gene therapies based on cell-to-cell delivery of RNA.


Assuntos
Técnicas Citológicas , Técnicas Genéticas , RNA , Animais , Transporte Biológico , Mamíferos/metabolismo , RNA/genética , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Vírus/genética , Tipagem Molecular , Análise de Sequência de RNA
5.
Annu Rev Biochem ; 90: 77-106, 2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-33784179

RESUMO

The faithful and timely copying of DNA by molecular machines known as replisomes depends on a disparate suite of enzymes and scaffolding factors working together in a highly orchestrated manner. Large, dynamic protein-nucleic acid assemblies that selectively morph between distinct conformations and compositional states underpin this critical cellular process. In this article, we discuss recent progress outlining the physical basis of replisome construction and progression in eukaryotes.


Assuntos
Replicação do DNA , DNA/biossíntese , Eucariotos/genética , Complexo de Reconhecimento de Origem/metabolismo , Animais , DNA/química , DNA Polimerase III/química , DNA Polimerase III/metabolismo , Humanos , Complexo de Reconhecimento de Origem/química , Complexo de Reconhecimento de Origem/genética , Antígeno Nuclear de Célula em Proliferação/química , Antígeno Nuclear de Célula em Proliferação/metabolismo
6.
Nat Immunol ; 25(1): 142-154, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38049580

RESUMO

Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.


Assuntos
Linfócitos B , Tecido Linfoide , Camundongos , Animais , Baço/metabolismo , Transdução de Sinais , Antígenos CD55/metabolismo , Eritrócitos
7.
Cell ; 184(25): 6119-6137.e26, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34890551

RESUMO

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Célula Única
8.
Cell ; 183(5): 1143-1146, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33128870

RESUMO

Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.


Assuntos
Senescência Celular , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Humanos , Modelos Biológicos
9.
Cell ; 181(2): 236-249, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302568

RESUMO

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Atlas como Assunto , Transformação Celular Neoplásica/patologia , Genômica/métodos , Humanos , Medicina de Precisão/métodos , Análise de Célula Única/métodos
10.
Cell ; 179(3): 619-631.e15, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31626768

RESUMO

DNA replication in eukaryotes generates DNA supercoiling, which may intertwine (braid) daughter chromatin fibers to form precatenanes, posing topological challenges during chromosome segregation. The mechanisms that limit precatenane formation remain unclear. By making direct torque measurements, we demonstrate that the intrinsic mechanical properties of chromatin play a fundamental role in dictating precatenane formation and regulating chromatin topology. Whereas a single chromatin fiber is torsionally soft, a braided fiber is torsionally stiff, indicating that supercoiling on chromatin substrates is preferentially directed in front of the fork during replication. We further show that topoisomerase II relaxation displays a strong preference for a single chromatin fiber over a braided fiber. These results suggest a synergistic coordination-the mechanical properties of chromatin inherently suppress precatenane formation during replication elongation by driving DNA supercoiling ahead of the fork, where supercoiling is more efficiently removed by topoisomerase II. VIDEO ABSTRACT.


Assuntos
Cromatina/química , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Torque , Cromatina/metabolismo , Replicação do DNA , DNA Super-Helicoidal/química , Células HeLa , Humanos , Pinças Ópticas , Saccharomyces cerevisiae
11.
Cell ; 178(3): 653-671.e19, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348890

RESUMO

Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.


Assuntos
Motivação/efeitos dos fármacos , Peptídeos Opioides/farmacologia , Recompensa , Área Tegmentar Ventral/metabolismo , Potenciais de Ação , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Precursores de Proteínas/genética , Receptores Opioides/agonistas , Receptores Opioides/deficiência , Receptores Opioides/genética , Receptor de Nociceptina , Nociceptina
12.
Annu Rev Cell Dev Biol ; 36: 411-440, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021826

RESUMO

Understanding human embryology has historically relied on comparative approaches using mammalian model organisms. With the advent of low-input methods to investigate genetic and epigenetic mechanisms and efficient techniques to assess gene function, we can now study the human embryo directly. These advances have transformed the investigation of early embryogenesis in nonrodent species, thereby providing a broader understanding of conserved and divergent mechanisms. Here, we present an overview of the major events in human preimplantation development and place them in the context of mammalian evolution by comparing these events in other eutherian and metatherian species. We describe the advances of studies on postimplantation development and discuss stem cell models that mimic postimplantation embryos. A comparative perspective highlights the importance of analyzing different organisms with molecular characterization and functional studies to reveal the principles of early development. This growing field has a fundamental impact in regenerative medicine and raises important ethical considerations.


Assuntos
Desenvolvimento Embrionário , Animais , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Humanos , Modelos Biológicos , Filogenia , Zigoto/metabolismo
13.
Immunity ; 57(3): 429-445, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38479360

RESUMO

Diverse inflammatory conditions, from infections to autoimmune disease, are often associated with cellular damage and death. Apoptotic cell death has evolved to minimize its inflammatory potential. By contrast, necrotic cell death via necroptosis and pyroptosis-driven by membrane-damaging MLKL and gasdermins, respectively-can both initiate and propagate inflammatory responses. In this review, we provide insights into the function and regulation of MLKL and gasdermin necrotic effector proteins and drivers of plasma membrane rupture. We evaluate genetic evidence that MLKL- and gasdermin-driven necrosis may either provide protection against, or contribute to, disease states in a context-dependent manner. These cumulative insights using gene-targeted mice underscore the necessity for future research examining pyroptotic and necroptotic cell death in human tissue, as a basis for developing specific necrotic inhibitors with the potential to benefit a spectrum of pathological conditions.


Assuntos
Apoptose , Gasderminas , Humanos , Animais , Camundongos , Necrose/metabolismo , Apoptose/fisiologia , Piroptose/fisiologia , Morte Celular , Inflamassomos/metabolismo , Proteínas Quinases/metabolismo
14.
Immunity ; 57(7): 1533-1548.e10, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38733997

RESUMO

Several interleukin-1 (IL-1) family members, including IL-1ß and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.


Assuntos
Caspase 1 , Microscopia Crioeletrônica , Interleucina-18 , Transdução de Sinais , Interleucina-18/metabolismo , Caspase 1/metabolismo , Humanos , Inflamassomos/metabolismo , Animais , Conformação Proteica , Ligação Proteica , Sítios de Ligação , Camundongos , Receptores de Interleucina-18/metabolismo , Modelos Moleculares , Peptídeos e Proteínas de Sinalização Intercelular
15.
Immunity ; 57(2): 287-302.e12, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38354704

RESUMO

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.


Assuntos
Antígenos CD28 , Redes Reguladoras de Genes , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Antígenos CD28/metabolismo , Transdução de Sinais , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Ligante CD27/genética , Ligante CD27/metabolismo , Linfócitos T CD8-Positivos
16.
Cell ; 173(2): 515-528.e17, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625057

RESUMO

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.


Assuntos
Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Mutação , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Medicina de Precisão , Transplante Heterólogo , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
17.
Cell ; 175(2): 530-543.e24, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30220458

RESUMO

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.


Assuntos
Nefrite Intersticial/virologia , Parvovirus/isolamento & purificação , Parvovirus/patogenicidade , Animais , Austrália , Progressão da Doença , Feminino , Fibrose/patologia , Fibrose/virologia , Humanos , Rim/metabolismo , Rim/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrite Intersticial/fisiopatologia , América do Norte , Infecções por Parvoviridae/metabolismo
18.
Cell ; 170(6): 1184-1196.e24, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886385

RESUMO

The bone morphogenetic protein (BMP) signaling pathway comprises multiple ligands and receptors that interact promiscuously with one another and typically appear in combinations. This feature is often explained in terms of redundancy and regulatory flexibility, but it has remained unclear what signal-processing capabilities it provides. Here, we show that the BMP pathway processes multi-ligand inputs using a specific repertoire of computations, including ratiometric sensing, balance detection, and imbalance detection. These computations operate on the relative levels of different ligands and can arise directly from competitive receptor-ligand interactions. Furthermore, cells can select different computations to perform on the same ligand combination through expression of alternative sets of receptor variants. These results provide a direct signal-processing role for promiscuous receptor-ligand interactions and establish operational principles for quantitatively controlling cells with BMP ligands. Similar principles could apply to other promiscuous signaling pathways.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Retroalimentação , Citometria de Fluxo , Ligantes , Camundongos , Modelos Biológicos , Células NIH 3T3
19.
Nat Immunol ; 20(8): 1059-1070, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308541

RESUMO

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Células Th1/patologia , Células Th17/patologia , Perfilação da Expressão Gênica , Infecções por HIV/virologia , Humanos , Receptores CXCR5/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia , Células Th17/imunologia , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
Cell ; 161(1): 176-176.e1, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25815994

RESUMO

The endoderm germ layer contributes to the respiratory and gastrointestinal (GI) lineages during development, giving rise to an array of specialized epithelial cell types lining organs, including the thyroid, thymus, lungs, liver, biliary system, pancreas, and intestines. This SnapShot timelines and summarizes key stages following gastrulation, including endoderm patterning, organ specification, and organogenesis. A lineage tree of the developing endocrine pancreas is outlined to further illustrate this process.


Assuntos
Trato Gastrointestinal/embriologia , Animais , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Humanos , Organogênese , Pâncreas/citologia , Pâncreas/embriologia , Pâncreas/metabolismo , Fatores de Transcrição/metabolismo
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