Dr Rebecca Gentek
How does the immune system develop in the embryo? What are the functions of embryonic immune cells? Does maternal adversity perturb immune development, and does this affect health in later life?
We are recruiting! We currently have openings for a Research Assistant [vacancy no 051383] and 2 Postdocs [vacancy no 015382], fully funded by the Kennedy Trust for Rheumatology Research.
We are also looking for motivated undergraduate and rotation students.
Interested? Send an informal enquiry comprising your CV, contact details of referees and a brief outline of your scientific interests and motivation to join the lab to Rebecca Gentek.
Ontogeny of the immune system
Blood cells develop in a complex sequence of events that involve different sites and time points. The first mature blood cells arise from progenitors generated early in embryogenesis. In most cases, these cells are gradually replaced through progenitors produced from other sources at later stages of embryonic development. Certain types of blood cells thus have different origins throughout life. They form what has been called a "layered" immune system. This has long been known for erythrocytes and megakaryocytes, and more recently found great appreciation for macrophages. It now appears to be more widely true, however, as it also applies to eg mast cells and innate lymphoid cells. The extent of this replacement varies between cell types and tissues. For example, many tissues retain a sizeable population of embryonic macrophages into adulthood. Other lineages, such as innate-like B1 and some gd T cells, are exclusively of embryonic origin, but can be replaced by or layered with similar cell types under specific conditions. Yet other lineages are constantly replenished in the adult from haematopoietic stem cells in the bone marrow, but these stem cells are themselves generated in the embryo.
While our understanding of immune development is improving, some exciting questions have remained largely unanswered: Do different layers of immune cells exert discrete, non-overlapping functions? Are layered cells and progenitors persisting into adulthood susceptible to environmental insults experienced in utero? How does this affect health in later life?
Developmental origins of adult disease: Programming of the immune system?
Indeed, it is now firmly established that the likelihood of developing chronic, non-communicable disease in adulthood is strongly influenced by environmental factors in early life, including the foetal period. This phenomenon, coined "programming", has been observed for maternal malnutrition and offspring cardiovascular and metabolic disease, but also other adversities and pathologies that involve the immune system, such as rheumatoid arthritis. Programming of the developing layered immune system might be the underlying cause.
Our research is centred on immune ontogeny: We study the development and functions of "layered" immune cells such as macrophages, mast cells and innate lymphocytes. We are particularly interested in the interplay between the intrauterine environment, immune development and health and disease in later life. Generous funding from the Kennedy Trust for Rheumatology Research enables us to explore the concept that the developing immune system is pathologically programmed in the context of rheumatoid arthritis.
We primarily use in vivo models that allow genetic fate mapping and conditional targeting of immune cells, as well as models mimicking maternal adversity and (rheumatoid) disease. These are interrogated with state-of-the-art readouts (eg single cell genomics, high-dimensional flow cytometry), and complemented with studies of human tissues.
During my undergraduate studies in Biology (Bochum, Germany), I developed a strong interest in cellular signalling pathways. This led me to join the group of Derk Amsen in Amsterdam (The Netherlands) as a PhD student, where I ventured into immunology and studied the differentiation of T cells and innate lymphocytes (ILC). To further pursue my budding passion for immune development, I moved to the CIML in Marseille (France) for my postdoc. My work with Michael Sieweke contributed to the recognition that embryonic macrophages can persist into adulthood and receive only low input from bone marrow progenitors. Working with Marc Bajenoff, I subsequently demonstrated that unlike previously thought, very similar developmental kinetics also apply to mast cells, whereas epidermal gd T cells are generated independently from adult-type progenitors altogether. Building on this work and the strong expertise on inflammatory disease, haematopoiesis and reproductive health concentrated in Edinburgh, I decided to start my own lab here. I joined CIR as a Chancellor's Fellow and obtained a Senior Research Fellowship from the Kennedy Trust shortly after.
Honours and Awards
- Research fellowship from the French heart foundation (2015)
- Scientist relocation grant from the City of Marseille (2014)
- Various travel grants to attend scientific conferences and symposia
- University graduation award of the Ruhr-University Bochum, annually awarded to the best graduate (Ruth-and-Gert-Massenberg-Foundation) (2008)
Mental Health First Aider (as of February 2020)
- Patrick Matthys (University of Leuven, Belgium)
- Nicolas Gaudenzio (University of Toulouse, France)
- Mohini Gray (CIR, University of Edinburgh)
- CRH and Tommy's Research Centre (University of Edinburgh)
Lymphatic Endothelial Cells Are Essential Components of the Subcapsular Sinus Macrophage Niche. Mondor I, Baratin M, Lagueyrie M, Saro L, Henri S, Gentek R, Suerinck D, Kastenmuller W, Jiang JX, Bajénoff M. Immunity. 2019 Jun 18; doi: 10.1016/j.immuni.2019.04.002. PMID: 31053503
Two distinct interstitial macrophage populations coexist across tissues in unique subtissular niches. Chakarov S, Lim HY, Tan L, Lim SY, See P, Lum J, Xiao-Meng Z, Foo S, Nakamizo S, Kaibo D, Kong WT, Gentek R, Balachander A, Carbajo D, Bleriot C, Malleret B, Tam JKC, Baig S, Shabeer M, Toh SAES, Schlitzer A, Larbi A, Marichal T, Malissen B, Chen J, Poidinger M, Kabashima K, Bajenoff M, Ng LG, Angeli V, Ginhoux F. Science. 2019 Mar 15; doi: 10.1126/science.aau0964. PMID: 30872492
Epidermal γδ T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult. Gentek R*, Ghigo C*, Hoeffel G*, Jorquera A, Msallam R, Wienert S, Klauschen F, Ginhoux F, Bajenoff M. *authors contributed equally. JEM. 2018 Nov 8; doi: 10.1084/jem.20181206. PMID: 30409784
Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells. Gentek R, Ghigo C, Hoeffel G, Bulle MJ, Msallam R, Gautier G, Launay P, Ginhoux F, Bajenoff M. Immunity. 2018 Jun 19; doi: 10.1016/j.immuni.2018.04.025. PMID: 29858009.
Developmental origin and maintenance of distinct testicular macrophage populations. Mossadegh-Keller N, Gentek R, Gimenez G, Bigot S, Mailfert S, Sieweke MH. JEM. 2017 Aug 7; doi: 10.1084/jem.20170829; PMID: 28784628
Sources of Funding
- Senior Research Fellowship from the Kennedy Trust for Rheumatology Research (starting 2020)
- Chancellor's Fellowship from the University of Edinburgh (2019)