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1.
Sci Immunol ; 7(68): eabi4919, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35179948

RESUMO

The response of naive CD8+ T cells to their cognate antigen involves rapid and broad changes to gene expression that are coupled with extensive chromatin remodeling, but the mechanisms governing these changes are not fully understood. Here, we investigated how these changes depend on the basic leucine zipper ATF-like transcription factor Batf, which is essential for the early phases of the process. Through genome scale profiling, we characterized the role of Batf in chromatin organization at several levels, including the accessibility of key regulatory regions, the expression of their nearby genes, and the interactions that these regions form with each other and with key transcription factors. We identified a core network of transcription factors that cooperated with Batf, including Irf4, Runx3, and T-bet, as indicated by their colocalization with Batf and their binding in regions whose accessibility, interactions, and expression of nearby genes depend on Batf. We demonstrated the synergistic activity of this network by overexpressing the different combinations of these genes in fibroblasts. Batf and Irf4, but not Batf alone, were sufficient to increase accessibility and transcription of key loci, normally associated with T cell function. Addition of Runx3 and T-bet further contributed to fine-tuning of these changes and was essential for establishing chromatin loops characteristic of T cells. These data provide a resource for studying the epigenomic and transcriptomic landscape of effector differentiation of cytotoxic T cells and for investigating the interdependency between transcription factors and its effects on the epigenome and transcriptome of primary cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Fatores Reguladores de Interferon/imunologia , Proteínas com Domínio T/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Epigênese Genética/genética , Feminino , Fatores Reguladores de Interferon/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas com Domínio T/genética
2.
ACR Open Rheumatol ; 3(3): 147-153, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33570829

RESUMO

OBJECTIVE: Vascular ultrasound (VUS) is a first-line test for giant cell arteritis (GCA) in Europe but has been of limited use in the United States. We report clinical experience with a multidisciplinary model of VUS for the evaluation of GCA at a large US medical center. METHODS: Patients who underwent VUS for evaluation of GCA between 2013 and 2017 were reviewed. Trained vascular technologists followed a standardized protocol to visualize bilateral temporal, carotid, subclavian, and axillary arteries. Vascular medicine physicians interpreted VUS as no arteritis, hyperechoic wall thickening, or acute arteritis. Characteristics of patients with versus without acute arteritis (no arteritis or hyperechoic wall thickening) were compared. Among patients with suspected new-onset GCA, the treating physician's pretest and posttest suspicion for GCA were compared. RESULTS: Of 530 patients, 10.6% had prior-onset GCA, 31.7% had polymyalgia rheumatica, and 57.6% were taking glucocorticoids. Most patients had no arteritis on VUS (84.3%); 10.6% had acute arteritis, and 5.1% had hyperechoic wall thickening. Typical GCA symptoms, such as jaw claudication and scalp tenderness, were significantly more frequent in patients with acute arteritis. For all 42 patients with suspected new-onset GCA and acute arteritis, posttest suspicion was unchanged or increased. Of 415 patients with suspected new-onset GCA and VUS without acute arteritis, suspicion decreased (76.4%) or was unchanged (20.2%). CONCLUSION: We describe a multidisciplinary model for incorporating VUS into GCA care. When pretest suspicion was low and VUS did not reveal acute arteritis, posttest suspicion typically decreased, whereas when pretest suspicion was high and VUS revealed acute arteritis, posttest suspicion was reinforced.

3.
Clin Exp Rheumatol ; 38 Suppl 124(2): 107-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32359038

RESUMO

OBJECTIVES: Literature describing follow-up vascular ultrasound (VUS) in giant cell arteritis (GCA) is limited. We report our experience with follow-up VUS obtained in clinical care of patients with GCA. METHODS: We retrospectively identified GCA patients with an abnormal initial VUS, defined as circumferential hypoechoic wall thickening ("halo sign"), or circumferential hyperechoic wall thickening without evidence of arteriosclerosis or arteritis, who subsequently underwent follow-up VUS during 2013-2018. Studies were interpreted as active arteritis, hyperechoic wall thickening without active arteritis, or no arteritis. We compared clinical and laboratory characteristics at time of initial VUS among patients with active arteritis vs. hyperechoic wall thickening without active arteritis. We described whether and how VUS interpretation changed from initial to follow-up VUS. Among individual vessels, we tested whether abnormal findings (e.g. halo sign) persisted at follow-up VUS using McNemar's test. RESULTS: 42 patients fulfilled study criteria. Median time between initial and follow-up VUS was 5.1 (IQR 2.6-7.9) months. Characteristics at initial VUS did not differ according to VUS interpretation. Among 36 patients with active arteritis on initial VUS, follow-up VUS showed active arteritis in 25.0%, hyperechoic wall thickening in 33.3% and no arteritis in 41.7%. Among 6 patients with hyperechoic wall thickening on initial VUS, half had no arteritis on follow-up VUS. Sonographic findings tended to persist in axillary arteries and were more likely to change in the superficial temporal arteries. CONCLUSIONS: Among 42 GCA patients, the majority had a change in VUS interpretation between initial and follow-up VUS. Sonographic findings in the temporal circulation more frequently changed than findings in axillary arteries.


Assuntos
Arterite de Células Gigantes/diagnóstico por imagem , Ultrassonografia , Artéria Axilar/diagnóstico por imagem , Artéria Axilar/patologia , Seguimentos , Arterite de Células Gigantes/patologia , Humanos , Estudos Retrospectivos , Artérias Temporais/diagnóstico por imagem , Artérias Temporais/patologia
4.
G3 (Bethesda) ; 8(8): 2825-2832, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29950427

RESUMO

The role of Notch signaling in cell-fate decisions has been studied extensively; however, this pathway is also active in adult tissues, including the nervous system. Notch signaling modulates a wide range of behaviors and processes of the nervous system in the nematode Caenorhabditis elegans, but there is no evidence for Notch signaling directly altering synaptic strength. Here, we demonstrate Notch-mediated regulation of synaptic activity at the C. elegans neuromuscular junction (NMJ). For this, we used aldicarb, an inhibitor of the enzyme acetylcholinesterase, and assessed paralysis rates of animals with altered Notch signaling. Notch receptors LIN-12 and GLP-1 are required for normal NMJ function; they regulate NMJ activity in an opposing fashion. Complete loss of LIN-12 skews the excitation/inhibition balance at the NMJ toward increased activity, whereas partial loss of GLP-1 has the opposite effect. Specific Notch ligands and co-ligands are also required for proper NMJ function. The role of LIN-12 is independent of cell-fate decisions; manipulation of LIN-12 signaling through RNAi knockdown or overexpression of the co-ligand OSM-11 after development alters NMJ activity. We demonstrate that LIN-12 modulates GABA signaling in this paradigm, as loss of GABA signaling suppresses LIN-12 gain-of-function defects. Further analysis, in vivo and in silico, suggests that LIN-12 may modulate transcription of the GABAB receptor GBB-2 Our findings confirm a non-developmental role for the LIN-12/Notch receptor in regulating synaptic signaling and identify the GABAB receptor GBB-2 as a potential Notch transcriptional target in the C. elegans nervous system.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Junção Neuromuscular/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Ácido gama-Aminobutírico/metabolismo , Aldicarb/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Inibidores da Colinesterase/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação , Junção Neuromuscular/efeitos dos fármacos , Receptores Notch/genética , Transdução de Sinais/efeitos dos fármacos
5.
Sleep ; 37(9): 1439-51, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25142568

RESUMO

OBJECTIVES: Cross-species conservation of sleep-like behaviors predicts the presence of conserved molecular mechanisms underlying sleep. However, limited experimental evidence of conservation exists. Here, this prediction is tested directly. MEASUREMENTS AND RESULTS: During lethargus, Caenorhabditis elegans spontaneously sleep in short bouts that are interspersed with bouts of spontaneous locomotion. We identified 26 genes required for Drosophila melanogaster sleep. Twenty orthologous C. elegans genes were selected based on similarity. Their effect on C. elegans sleep and arousal during the last larval lethargus was assessed. The 20 most similar genes altered both the quantity of sleep and arousal thresholds. In 18 cases, the direction of change was concordant with Drosophila studies published previously. Additionally, we delineated a conserved genetic pathway by which dopamine regulates sleep and arousal. In C. elegans neurons, G-alpha S, adenylyl cyclase, and protein kinase A act downstream of D1 dopamine receptors to regulate these behaviors. Finally, a quantitative analysis of genes examined herein revealed that C. elegans arousal thresholds were directly correlated with amount of sleep during lethargus. However, bout duration varies little and was not correlated with arousal thresholds. CONCLUSIONS: The comprehensive analysis presented here suggests that conserved genes and pathways are required for sleep in invertebrates and, likely, across the entire animal kingdom. The genetic pathway delineated in this study implicates G-alpha S and previously known genes downstream of dopamine signaling in sleep. Quantitative analysis of various components of quiescence suggests that interdependent or identical cellular and molecular mechanisms are likely to regulate both arousal and sleep entry.


Assuntos
Caenorhabditis elegans/fisiologia , Sequência Conservada , Dopamina/metabolismo , Drosophila melanogaster/fisiologia , Transdução de Sinais/genética , Sono/genética , Sono/fisiologia , Animais , Animais Geneticamente Modificados , Nível de Alerta/genética , Nível de Alerta/fisiologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Calcineurina/metabolismo , Proteínas Culina/genética , Proteínas Culina/metabolismo , AMP Cíclico/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Genes de Helmintos , Genes de Insetos , Larva/genética , Larva/fisiologia , Locomoção/fisiologia , Modelos Animais , Neurônios/metabolismo , Neurotransmissores/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Descanso/fisiologia , Superfamília Shaker de Canais de Potássio/genética , Superfamília Shaker de Canais de Potássio/metabolismo
6.
Nat Immunol ; 15(4): 373-83, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24584090

RESUMO

The transcription factor BATF is required for the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and follicular helper T cells (TFH cells). Here we identified a fundamental role for BATF in regulating the differentiation of effector of CD8(+) T cells. BATF-deficient CD8(+) T cells showed profound defects in effector population expansion and underwent proliferative and metabolic catastrophe early after encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins, bound to and promoted early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors and augments the propagation of inflammatory signals but restrains the expression of genes encoding effector molecules. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proteínas com Domínio T/metabolismo , Células Th17/imunologia , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Diferenciação Celular/genética , Processos de Crescimento Celular/genética , Células Cultivadas , Regulação para Baixo , Granzimas/genética , Granzimas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética
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