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Immunol Cell Biol ; 96(10): 1060-1071, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29790605


Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

Antígenos CD57/metabolismo , Diferenciação Celular , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Encurtamento do Telômero , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Citocinas/metabolismo , Humanos , Imunofenotipagem , Contagem de Linfócitos , Sirolimo/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos
Cell ; 171(2): 385-397.e11, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28919076


T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.

Antígenos CD28/metabolismo , Ativação Linfocitária , Mitocôndrias/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Carnitina O-Palmitoiltransferase , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/farmacologia , Humanos , Interleucina-15/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/metabolismo , Estresse Fisiológico , Linfócitos T/metabolismo
Mol Cell Biol ; 24(5): 2153-68, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14966293


Using a yeast two-hybrid screen, we identified human nucleosome assembly protein 1 (hNAP-1) as a protein interacting with the activation domain of the transcriptional activator encoded by papillomaviruses (PVs), the E2 protein. We show that the interaction between E2 and hNAP-1 is direct and not merely mediated by the transcriptional coactivator p300, which is bound by both proteins. Coexpression of hNAP-1 strongly enhances activation by E2, indicating a functional interaction as well. E2 binds to at least two separate domains within hNAP-1, one within the C terminus and an internal domain. The binding of E2 to hNAP-1 is necessary for cooperativity between the factors. Moreover, the N-terminal 91 amino acids are crucial for the transcriptional activity of hNAP-1, since deletion mutants lacking this N-terminal portion fail to cooperate with E2. We provide evidence that hNAP-1, E2, and p300 can form a ternary complex efficient in the activation of transcription. We also show that p53 directly interacts with hNAP-1, indicating that transcriptional activators in addition to PV E2 interact with hNAP-1. These results suggest that the binding of sequence-specific DNA binding proteins to hNAP-1 may be an important step contributing to the activation of transcription.

Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares , Proteínas/metabolismo , Transativadores/metabolismo , Transcrição Genética , Ativação Transcricional , Proteínas Virais/metabolismo , Acetiltransferases/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Genes Reporter , Histona Acetiltransferases , Humanos , Substâncias Macromoleculares , Proteína 1 de Modelagem do Nucleossomo , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Proteínas Virais/genética , Fatores de Transcrição de p300-CBP
J Mol Evol ; 56(5): 597-606, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12698296


Comparison of histone gene cluster arrangements in several species has revealed a broad spectrum of histone gene patterns. To elucidate the core histone gene organization in a mollusk, we have analyzed a Mytilus edulis genomic library and have isolated eight phage clones containing core histone genes. Analysis of insert DNA revealed that the core histone genes are arranged as regular gene repeats of all four core histones. The repeats do not contain linker histone genes. The clones are distributed into two groups of dissimilar repeated units with a common size of about 5.6 kb. The genes of each core histone class in the distinct repeats encode identical histone proteins and have comparable gene arrangements in the two repeat units. However, the intergenic sequences differ significantly. The core histone genes are organized as large clusters of about 100 repeats each. Previously, we have shown that the linker histone genes in M. edulis are also organized in a cluster of repeats of solitary H1 genes. Hence, this is the first case of a separate, clustered organization of both core and linker histone genes, respectively.

Bivalves/genética , Histonas/genética , Família Multigênica , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Recombinante/análise , Biblioteca Genômica , Histonas/química , Histonas/isolamento & purificação , Humanos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Ratos , Mapeamento por Restrição , Análise de Sequência de DNA , Sequências de Repetição em Tandem/genética