RESUMO
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.
Assuntos
Células Apresentadoras de Antígenos/metabolismo , Tolerância Imunológica , Memória Imunológica , Linfonodos/metabolismo , Fatores de Transcrição NFATC/genética , Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Comunicação Celular , Diferenciação Celular , Movimento Celular , Núcleo Celular/metabolismo , Citosol/metabolismo , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/imunologia , Regulação da Expressão Gênica , Humanos , Interferon gama/genética , Interferon gama/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Fatores de Transcrição NFATC/imunologia , Transporte Proteico , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Linfócitos T/imunologia , Células Tumorais CultivadasRESUMO
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.