- Tomasello Elena - "Studying the functions of plasmacytoid dendritic cells at the homeostasis and during inflammation"
The host laboratory is the “Dendritic cells and anti-viral defense” headed by Dr. Marc Dalod, at the CIML. The PhD project will be performed under the direct supervision of Dr. Elena Tomasello, directing a research group working on plasmacytoid dendritic cells. The PhD project has been submitted to the annual PhD context of the Ecole Doctorale Sciences de la Vie et de la Santé, Aix-Marseille University.
Plasmacytoid dendritic cells (pDCs) are a major source of type I and type III interferons (IFNs) during many systemic viral infections1 ,2. The response to IFNs is essential to promote antiviral immunity, so pDCs are considered to be key in this process3. pDC reside in both lymphoid (bone marrow, spleen, lymph nodes and thymus) and non-lymphoid (liver and gut) organs. During infection with murine cytomegalovirus (MCMV), the virus spreads in the whole body, but only splenic pDCs produce IFN 4. In contrast, pDCs residing in the liver and the intestine would be rather involved in tolerance by inducing regulatory T cells (Treg)5. Therefore, pDC exert immunoactivating or immunosuppressive functions depending on their organ of residence. Recently, it has been shown that each organ has a specific cell "niche" that instructs resident macrophages to perform functions specific to that tissue6. It remains to be determined whether and how the concept of "niche" could be extended to pDCs.
The functions of pDCs also vary according to the disease context. We have recently shown that, during MCMV infection, splenic pDCs producing IFN acquire at least 5 distinct activation states at the transcriptional level that are differentially regulated at the spatio-temporal level. Thus, during IFN production, pDCs (stages 1-3) are located in the marginal zone, in close proximity to the infected cells, whereas, once they have ceased IFN production, the ex-IFN-producing pDCs (stages 4-5) acquire phenotypic and functional properties of antigen presenting cells, express CCR7 and migrate to the T cell zone7. The presence of pDCs in early tumour stages is associated with better survival, suggesting immunoactivating functions8. On the other hand, in advanced and invasive cancers, the tumour microenvironment promotes immunosuppressive functions in tumor-infiltrating pDCs9. Finally, the immunoactivating functions of pDCs are beneficial in tissue repair10, but harmful in many autoimmune diseases 11. Identifying the molecular mechanisms and cellular actors involved in instruction of pDC functions is thus crucial to modulate their activation in the most appropriate manner according to the pathology studied.
- Tomasello, E., Pollet, E., Vu Manh, T. P., Uze, G. & Dalod, M. Front Immunol 5, 526, doi:10.3389/fimmu.2014.00526 (2014).
- Tomasello, E. et al. EMBO J 37, doi:10.15252/embj.201798836 (2018).
- Reizis, B. P Immunity 50, 37-50, doi:10.1016/j.immuni.2018.12.027 (2019).
- Zucchini, N. et al. Int Immunol 20, 45-56, doi:10.1093/intimm/dxm119 (2008).
- Swiecki, M. & Colonna, M. TNat Rev Immunol 15, 471-485, doi:10.1038/nri3865 (2015).
- Guilliams, M., Thierry, G. R., Bonnardel, J. & Bajenoff, M. mmunity 52, 434-451, doi:10.1016/j.immuni.2020.02.015 (2020).
- Abbas, A. et al. Nat Immunol 21, 983-997, doi:10.1038/s41590-020-0731-4 (2020).
- Michea, P. et al. Nat Immunol 19, 885-897, doi:10.1038/s41590-018-0145-8 (2018).
- Sisirak, V. et al. I Cancer Res 72, 5188-5197, doi:10.1158/0008-5472.CAN-11-3468 (2012).
- Di Domizio, J. et al. Nat Immunol 21, 1034-1045, doi:10.1038/s41590-020-0721-6 (2020).
- Sisirak, V. et al. J Exp Med 211, 1969-1976, doi:10.1084/jem.20132522 (2014).
- Luci, C. et al. Nat Immunol 10, 75-82, doi:10.1038/ni.1681 (2009).
- Reynders, A. et al. EMBO J 30, 2934-2947, doi:10.1038/emboj.2011.201 (2011).
Main objectives of the research project
Our main objective is to determine how the functions of pDCs are modulated by their tissue environment at homeostasis and in pathological conditions (MCMV infection, dysbiosis, breast cancer). We will use unique mouse models (manuscripts in preperation) allowing to specifically identify “bona fide” pDC by fluorescence (pDC-TdT mice) or specifically and constitutively deplete them (pDC-less mice). To address our questions, we will use a systems biology approach, combining multiparametric flow cytometry and confocal spectral microscopy with cutting edge genomics technologies, including generation and advanced bioinformatics analyses of spatial transcriptomics, single cell or single nucleus RNA sequencing (scRNA-Seq, snRNA-Seq).
The candidate must have a Master 2 in Immunology or equivalent, have already acquired experience in handling mice (training in animal experimentation at the “applicateur” level, former Level II, is recommanded) and accept the necessity and constraints of animal experimentation (daily monitoring of mice subjected to experimental protocols, evaluation of potential animal suffering and knowledge of its limit points). He (she) should be highly motivated and hard-working, very rigorous and respectful of the established protocols and have excellent organizational skills. He (she) will also have to be a team player, contribute to the chores necessary for the smooth running of the laboratory, be respectful of his (her) supervisors, knowing how to accept criticism and to question himself (herself) if necessary. An interest in learning bioinformatics analysis of the data generated will be particularly appreciated.
Documents required for application
•transcript of your MSc's grades (M1 and M2 if available)
The Laboratory of Genetic dissection of the function of T cells and dendritic cells seeks a highly motivated PhD student, within the context of the 2021 PhD call of the “INSTITUT CANCER ET IMMUNOLOGIE” (ICI) https://www.univ-amu.fr/fr/public/call-phd-application-institut-cancer-et-immunologie-ici. The project will be headed by Dr. Romain Roncagalli, within Centre d’Immunologie de Marseille Luminy (CIML, Marseille, France, http://www.ciml.univ-mrs.fr/). The CIML is a research institute internationally renowned and highly attractive for young scientist.
T lymphocytes play a key role in immunity and their functions are intimately linked to metabolic programs. Understanding the signaling pathways regulating metabolism changes is of crucial interest to offer novel therapeutic opportunities in the context of T cell reprogramming. Using an original mouse model the student will be in charge of characterizing a novel metabolic effectors in order to reprogram the effector functions of T lymphocytes during anti-cancer responses.
Efficient immune responses against malignant cells are the result of complex and highly coordinated cellular processes. Over the past decades, major research efforts have shown that T cells play a central role in the development of these processes. T cell activation is intimately linked to metabolic activities. The primary antigen response is characterized by a T cell shift to a state of metabolic activation characterized by high rates of aerobic glycolysis called the Warburg effect, which promotes increased nutrient uptake and macromolecular biosynthesis. This process is fundamental for cell growth, differentiation and T cell effector functions and dictates the extent of the immune response against cancer cells. In this regards, identifying and controlling effectors of the AKT-mTOR signaling pathway has emerged of a promising strategy to modify T cell metabolism and thus their effector functions.
Using a global phosphoproteomic approach, we recently identified the transcription factor Foxk1 as a potential target to reprogram T cell metabolism in order to improve anti-cancer responses. Foxk1 is a substrate of the AKT-mTor kinases and is a critical regulator of metabolism in non- hematopoietic cells. Our preliminary results indicated that Foxk1 may have similar functions in T cells. Using Foxk1 knock-out mouse, the project will consist in dissecting the functions of Foxk1 in the context of anti-cancer T-cell responses.
Candidates will be evaluated based on the following criteria:
• Academic achievements
• Past research experience (internships, master thesis)
• Interest to work in a multidisciplinary research environment
• Enthusiasm and communication skills
Documents required for application:
•transcript of your MSc's grades (M1 and M2 if available)
Contact: Romain Roncagalli
Stages pour les étudiants de 1er et 2ème cycle
Le CIML propose un nombre limité de stages à des étudiants de 1er ou 2ème cycle universitaire. Pour postuler à ces stages, les demandes doivent être adressées directement aux Responsables d'Equipes ou de Plateformes, en fonction de l'intérêt des étudiants pour les projets de recherche et les expertises technologiques.