Immunoreceptor mertk: a journey from the membrane into the nucleus of human dendritic cells
- Autores: Kyra J.E. Borgman
- Directores de la Tesis: Maria Garcia Parajo (dir. tes.), Daniel Benítez Ribas (codir. tes.), Annabel Fernández Valledor (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Alessandra Cambi (presid.), Felix Campelo Aubarell (secret.), Ignacio Izzedin (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Discrimination between foreign and potentially harmful antigens, and the body’s own tissue is one of the most crucial first steps that lays at the basis of a proper immune response. Immunoreceptors are cell membrane embedded molecules that aid immune cells in identifying and interacting with its environment. Because of their key importance, they are therefore a frequent subject of research in immunology. It is becoming increasingly clear that the organization of immunoreceptors in space and time on the plasma membrane directly impacts on the way they function. Over the past two decades, novel microscopy techniques and biophysical tools have been developed and exploited to directly visualize molecular events in immune cells with unprecedented spatial and temporal resolution. These technical advances have led to the emergence of a new, active field of research: Nano-immunology. Biophysical tools and super-resolution imaging have been exploited in this thesis to unravel the spatiotemporal behaviour of different immunoreceptors, with a particular emphasis on the tyrosine kinase immunoreceptor MerTK. These studies have contributed to further our understanding of immune cell biology at the molecular level.
In Part I of this thesis, I will discuss several advanced imaging techniques and microfabrication approaches that I used throughout my doctoral studies. For each technique, the fundamental principles as well as the quantitative analysis associated to them will be explained. Their specific advantages in the field of nano-immunology will be highlighted. In addition, an example of how each technique has been exploited to answer a specific biological question in the field will be given. All of the examples presented in part I correspond to publications that I co-authored during my PhD research.
In Part II, I will address the subcellular organization of the immunoreceptor MerTK in human dendritic cells (DCs). By exploiting super-resolution STED nanoscopy, we discovered that MerTK organizes in small nanoclusters on the plasma membrane of tolerogenic DCs, where MerTK is highly expressed. Moreover, we will show that even though MerTK is a membrane receptor, it is also found at very high levels in the nucleus of DCs. To place this finding in the context of immunity, we established a direct correlation between DC differentiation and the amount of MerTK found in the nucleus. We enquired the route by which MerTK translocate to the nucleus, and dissected some of the main molecular factors involved in promoting this translocation. In a first attempt to identify its nuclear function, we additionally mapped the spatial relationship between MerTK and chromatin with nanometre accuracy using super-resolution STORM nanoscopy, in single intact DCs nuclei at different stages of their differentiation. We will finally place our findings in a broader perspective and suggest future lines of investigation that may further unravel the molecular mechanism of action of MerTK in particular, and the functional role of membrane receptors in the nucleus in general.
