RESUMEN
Naive CD4+ T cells activated through TCR/CD28 under Th1 or Th2 conditions expressed canonical cytokine patterns irrespective of cell division. Only cells that had divided fewer than four times were capable of reexpressing alternative cytokines when restimulated under opposing conditions. Although T cells transcribed both IFN-gamma and IL-4 within hours in a Stat4-/Stat6-independent manner, neither T-bet nor GATA-3 was induced optimally without Stat signals, and polarized cytokine expression was not sustained. Cytokine genes were positioned apart from heterochromatin in resting T cell nuclei, consistent with rapid expression. After polarization, the majority of silenced cytokine alleles were repositioned to heterochromatin. Naive T cells transit through sequential stages of cytokine activation, commitment, silencing, and physical stabilization during polarization into differentiated effector subsets.
Asunto(s)
Diferenciación Celular , Citocinas/genética , Silenciador del Gen , Células TH1/metabolismo , Células Th2/metabolismo , Transcripción Genética/genética , Alelos , Animales , División Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Factor de Transcripción GATA3 , Eliminación de Gen , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Heterocromatina/genética , Heterocromatina/metabolismo , Interferón gamma/genética , Interleucina-4/genética , Interleucina-5/genética , Cinética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Factor de Transcripción STAT4 , Factor de Transcripción STAT6 , Proteínas de Dominio T Box , Células TH1/citología , Células TH1/inmunología , Células Th2/citología , Células Th2/inmunología , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Transgenes/genéticaRESUMEN
Interleukins -4, -5, and -13, cardinal cytokines produced by Th2 cells, are coordinately expressed and clustered in 150-kb syntenic regions on mouse chromosome 11 and human chromosome 5q31. We analyzed two sets of human yeast artificial chromosome transgenic mice that contained the 5q31 cytokines to assess whether conserved sequences required for their coordinate and cell-specific regulation are contained within the cytokine cluster itself. Human IL-4, IL-13, and IL-5 were expressed under Th2, but not Th1, conditions in vitro. Each of these cytokines was produced during infection with Nippostrongylus brasiliensis, a Th2-inducing stimulus, and human IL-4 was generated after activation of NK T cells in vivo. Consistently fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. These data imply the existence of both conserved trans-activating factors and cis-regulatory elements that underlie the coordinate expression and lineage specificity of the type 2 cytokine genes in lymphocytes.
Asunto(s)
Cromosomas Humanos Par 5/inmunología , Citocinas/biosíntesis , Citocinas/genética , Regulación de la Expresión Génica/inmunología , Familia de Multigenes , Transgenes/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Cromosomas Humanos Par 5/genética , Citocinas/administración & dosificación , Citocinas/fisiología , Humanos , Interleucina-4/biosíntesis , Líquido Intracelular/inmunología , Líquido Intracelular/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Microinyecciones , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Two unrelated females, age 15 and 5 years respectively, were studied cytogenetically because of severe mental retardation, seizures and ataxia-like incoordination. A similar deletion of the proximal long arm of chromosome 15 was found in both patients. Re-evaluation showed no voracious appetite or obesity; normal size of hands and feet, minimal to no hypotonia by history or examination and facial features not typical of the Prader-Willi syndrome. However, the facial appearance of the girls was similar to each other with mild hypertelorism. The similarity of these girls and dissimilarity to Prader-Willi syndrome suggest a different syndrome, perhaps the result of deletion of a different segment of 15q. The findings of ataxic-like movements, frequent, unprovoked and prolonged bouts of laughter and facial appearance are more compatible with the diagnosis of Angelman syndrome.