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1.
Cell ; 171(2): 385-397.e11, 2017 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-28919076

RESUMEN

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.


Asunto(s)
Antígenos CD28/metabolismo , Activación de Linfocitos , Mitocondrias/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Carnitina O-Palmitoiltransferasa , Inhibidores Enzimáticos/farmacología , Compuestos Epoxi/farmacología , Humanos , Interleucina-15/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/metabolismo , Estrés Fisiológico , Linfocitos T/metabolismo
2.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29790605

RESUMEN

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.


Asunto(s)
Antígenos CD57/metabolismo , Diferenciación Celular , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Acortamiento del Telómero , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Senescencia Celular/genética , Senescencia Celular/inmunología , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Citocinas/metabolismo , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Enfermedades de Inmunodeficiencia Primaria , Sirolimus/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos
3.
J Exp Med ; 218(2)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33170215

RESUMEN

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαß+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.


Asunto(s)
ADP-Ribosil Ciclasa 1/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos Comunes de Leucocito/metabolismo , Receptor fas/inmunología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Activación de Linfocitos/inmunología , Trastornos Linfoproliferativos/inmunología , Masculino , Persona de Mediana Edad , Transducción de Señal/inmunología , Adulto Joven
4.
Mol Cell Biol ; 24(5): 2153-68, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14966293

RESUMEN

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.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares , Proteínas/metabolismo , Transactivadores/metabolismo , Transcripción Genética , Activación Transcripcional , Proteínas Virales/metabolismo , Acetiltransferasas/metabolismo , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Proteínas de Unión al ADN/genética , Genes Reporteros , Histona Acetiltransferasas , Humanos , Sustancias Macromoleculares , Proteína 1 de Ensamblaje de Nucleosomas , Unión Proteica , Estructura Terciaria de Proteína , Proteínas/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Factores de Transcripción de Dominio TEA , Transactivadores/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Técnicas del Sistema de Dos Híbridos , Proteínas Virales/genética , Factores de Transcripción p300-CBP
5.
J Gen Virol ; 81(Pt 8): 1975-1981, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10900036

RESUMEN

Genital human papillomaviruses (HPV) are considered to be one of the main risk factors for the development of cervical cancer. The P97 promoter at the E6-proximal end of the long control region (LCR) regulates the transcription of viral genes, especially the oncogenes E6 and E7. The LCR contains binding sites of several viral and cellular transcription factors, which either activate or repress the P97 promoter. Intratype variants of HPV-16 belong to six geographically clustered phylogenetic groups distributed all over the world. These variants exhibit differences in E6 protein activities and in tumour progression in vivo. Seven HPV-16 variants were investigated by sequencing the entire LCR (nt 7060-124) and by comparing the transcriptional activities of their P97 promoters. Previously unknown nucleotide variations were identified in all LCRs investigated. In luciferase assays, 3.3- and 2.8-fold increases in P97 promoter activity were detected in the Asian American c and North American 1 variants when compared with the European reference clone. The African variants 1a and 2a exhibited P97 promoter activities comparable to the European reference clone. After recombining different LCR fragments, the region responsible for enhanced transcription in the Asian American c and North American 1 variants could be attributed to the E6-proximal end of the LCR (nt 7619-124).


Asunto(s)
Proteínas Oncogénicas Virales/genética , Papillomaviridae/genética , Regiones Promotoras Genéticas , Proteínas Represoras , Secuencia de Bases , Humanos , Proteínas Oncogénicas Virales/química , Células Tumorales Cultivadas
6.
J Mol Evol ; 56(5): 597-606, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12698296

RESUMEN

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.


Asunto(s)
Bivalvos/genética , Histonas/genética , Familia de Multigenes , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Recombinante/análisis , Biblioteca Genómica , Histonas/química , Histonas/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Ratas , Mapeo Restrictivo , Análisis de Secuencia de ADN , Secuencias Repetidas en Tándem/genética
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