Kinetik und Mechanismen der Migration dendritischer Zellen im Steady-State
Zusammenfassung der Projektergebnisse
Dendritic cells (DCs) are key cells of the immune system and are present in nearly all tissues of the body. They control the development of new immune responses against pathogens but also act to prevent inflammatory immune responses against harmless substances such as those from food or even symbiotic gut bacteria. Crucial for DC function is their ability to migrate from peripheral tissues, such as the skin and intestine, to the local lymphoid tissues, principally the lymph nodes (LNs). LNs are specialised tissues that allow the induction of new immune responses by activation of naïve T cells and B cells. DCs are able to migrate through lymphatic vessels and transfer information from peripheral organs to the LN, signalling to the T cells and B cells what kind of response (i.e. immunity or tolerance) is needed. Crucially, DCs also act as Antigen Presenting Cells (APCs) by displaying antigens, fragments of foreign proteins, to T cells. Therefore, DC migration acts as unique link between peripheral and lymphoid tissues and is essential for proper activation of T cell responses. However, despite its importance, much remains to be understood about DC migration on a fundamental level. In this project, we used cutting-edge experimental methods to characterise the kinetics of DC migration and molecular processes that control it. By using a transgenic mouse expressing the light-sensitive fluorescent marker Dendra-2, we were able to track the kinetics of DC migration in mice in the steady state. We found that nearly the entire population of migratory LN DCs is replaced every single day by newly arriving DCs from the periphery. This means that the organism spends considerable resources to maintain a steady stream of DCs migrating from tissues to the LN, underlining the importance of this process. We also characterised the kinetics at all stages of the DC life cycle and found that replacement of DCs in peripheral tissues depends on recruitment of new precursors as well as substantial local proliferation. We are currently using all the information to construct a coherent mathematical model of DC migration. In addition, we analysed intestinal DCs using single-cell RNA sequencing, which provided a detailed profile of the transcriptional program of DCs along their maturation stages and revealed huge changes in DCs that had made the decision to migrate out of the peripheral tissue. Finally, we used this information to screen for candidate molecular pathways controlling DC migration and perform experiments to directly test their involvement. In summary, our work offers a detailed understanding of the molecular processes and intracellular changes involved in DC migration and provides a list of candidates molecular pathways which could be used to manipulate DC migration, in order to enhance or prevent the induction of specific immune responses. Moreover, the detailed description of DC migration kinetics increases our general understanding of this fundamental biological process and will provide a basis for further research, both basic and translational.
Projektbezogene Publikationen (Auswahl)
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Dendritic cell functions in the inductive and effector sites of intestinal immunity. Mucosal Immunology, 15(1), 40-50.
Luciani, Cécilia; Hager, Fabian Tobias; Cerovic, Vuk & Lelouard, Hugues
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Enhanced cultured diversity of the mouse gut microbiota enables custom-made synthetic communities. Cell Host & Microbe, 30(11), 1630-1645.e25.
Afrizal, Afrizal; Jennings, Susan A.V.; Hitch, Thomas C.A.; Riedel, Thomas; Basic, Marijana; Panyot, Atscharah; Treichel, Nicole; Hager, Fabian T.; Wong, Erin Oi-Yan; Wolter, Birger; Viehof, Alina; von Strempel, Alexandra; Eberl, Claudia; Buhl, Eva M.; Abt, Birte; Bleich, André; Tolba, René; Blank, Lars M.; Navarre, William W. ... & Clavel, Thomas
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Stabilization but No Functional Influence of HIF-1α Expression in the Intestinal Epithelium during Salmonella Typhimurium Infection. Infection and Immunity, 90(2).
Robrahn, Laura; Dupont, Aline; Jumpertz, Sandra; Zhang, Kaiyi; Holland, Christian H.; Guillaume, Joël; Rappold, Sabrina; Roth, Johanna; Cerovic, Vuk; Saez-Rodriguez, Julio; Hornef, Mathias W. & Cramer, Thorsten
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MHCII expression on gut macrophages supports T cell homeostasis and is regulated by microbiota and ontogeny. Scientific Reports, 13(1).
Guillaume, Joël; Leufgen, Andrea; Hager, Fabian T.; Pabst, Oliver & Cerovic, Vuk
