Immune surveillance of neural stem cells

• Autores: P. J. Martí Rodrigo
• Directores de la Tesis: María Isabel Fariñas Gómez (dir. tes.), Alberto Yáñez Boyer (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2022
• Idioma: inglés
• Tribunal Calificador de la Tesis: María Ángeles Vicente López (presid.), María Luisa Gil Herrero (secret.), Óscar Fernández Capetillo (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Inmunología
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• Resumen

  • Antigen presentation through major histocompatibility complexes and the subsequent immune surveillance by cytotoxic T lymphocytes is considered a preventive mechanism against damaged or infected cells. At the same time, the central nervous system has long been considered an isolated territory where immune responses could not be fully developed. However, in the light of recent findings, these assumptions need to be revisited. On one hand, it has been demonstrated that quiescent adult stem cells down-regulate antigen exposure and evade immune surveillance in the hair follicle and the muscle. On the other hand, the identification of lymphatic routes for the drainage of brain-derived antigens have challenged the concept of brain immune privilege, and it is now assumed that the formation of neoantigens in neural cells is constantly monitored by the immune system. Specifically, the subependymal zone is the largest neurogenic niche in the adult mammalian brain and contains neural stem cells that can either be in a quiescence or in an activated state. The latter proliferate to give rise to the neurogenic lineage that generates mainly neurons for the olfactory bulb or small numbers of glial cells for the corpus callosum or the striatum. In addition, subependymal neural stem cells have been identified as the cells-of-origin of primary glioblastoma, the most aggressive form of brain tumor. However, whether adult neural stem cells undergo immune surveillance had not been studied before and we decided to explore it by using the adoptive transfer of T lymphocytes engineered to kill cells that express the green fluorescent protein in transgenic mice, in which this reporter protein is specifically expressed in the subependymal neurogenic lineage. Our results indicate that activated neural stem cells can be eliminated by T lymphocytes, while the quiescent ones evade immune surveillance. The analysis of antigen presentation and other mediators of cellular immunity reveals that the susceptibility of neural stem cells to T lymphocyte-mediated killing is determined by a finely tuned balance between activation signals, essentially major histocompatibility complexes exposure, and inhibitory mechanisms that include immune checkpoints and protective mechanisms. Also, we demonstrate that antigen presentation is subjected to post-translational regulation and depends on CD99 expression in some neural stem cells.