RESUMEN
Interactions with antigen-presenting cells (APCs) interrupt T cell migration through tissues and trigger signaling pathways that converge on the activation of transcriptional regulators, including nuclear factor of activated T cells (NFAT), which control T cell function and differentiation. Both stable and unstable modes of cognate T cell-APC interactions have been observed in vivo, but the functional significance of unstable, serial contacts has remained unclear. Here we used multiphoton intravital microscopy in lymph nodes and tumors to show that while NFAT nuclear import was fast (t(1/2 max)â¼1 min), nuclear export was slow (t(1/2)â¼20 min) in T cells. During delayed export, nuclear NFAT constituted a short-term imprint of transient TCR signals and remained transcriptionally active for the T cell tolerance gene Egr2, but not for the effector gene Ifng, which required continuous TCR triggering for expression. This provides a potential mechanistic basis for the observation that a predominance of unstable APC interactions correlates with the induction of T cell tolerance.
Asunto(s)
Células Presentadoras de Antígenos/metabolismo , Tolerancia Inmunológica , Memoria Inmunológica , Ganglios Linfáticos/metabolismo , Factores de Transcripción NFATC/genética , Linfocitos T/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/patología , Comunicación Celular , Diferenciación Celular , Movimiento Celular , Núcleo Celular/metabolismo , Citosol/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Regulación de la Expresión Génica , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica , Factores de Transcripción NFATC/inmunología , Transporte de Proteínas , Receptores de Antígenos de Linfocitos T , Transducción de Señal , Linfocitos T/inmunología , Células Tumorales CultivadasRESUMEN
Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that ERMS-propagating potential is confined to myf5+ cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ ERMS cells reside adjacent normal muscle fibers. By late-stage ERMS, myf5+ cells are reorganized into distinct regions separated from differentiated tumor cells. Time-lapse imaging of late-stage ERMS revealed that myf5+ cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. Moreover, myogenin+ ERMS cells can enter the vasculature, whereas myf5+ ERMS-propagating cells do not. Our data suggest that non-tumor-propagating cells likely have important supportive roles in cancer progression and facilitate metastasis.