Postdoctoral Associate Researcher - What are the physiological functions of plasmacytoid dendritic

What are the physiological functions of plasmacytoid dendritic cells and how are they molecularly regulated?
 
 

Scientific background for the project

Plasmacytoid dendritic cells (pDC) are characterized by rapid, high production of type I and III interferons in response to viruses. They can also contribute to tissue repair and immune tolerance. Hence, they may promote health over disease by limiting viral replication, promoting wound healing and preventing allergies or auto-immune diseases. When deregulated, pDC functions can become deleterious by inhibiting anti-tumoral immune responses or promoting the development of interferon-dependent inflammatory diseases. However, the physiological role of pDC remains enigmatic. Even the extent to which their interferon production is critical for antiviral immunity, and how, is controversial. This is due to a major technical limitation: the lack of proper tools to visualize, constitutively deplete or genetically manipulate pDC in vivo. To overcome this bottleneck, we have generated mutant mouse strains and will use them to decipher pDC physiological functions and their molecular regulation.
 
 

Specific objectives of the research program

The applicant will use novel reporter mice combined with single cell RNA sequencing to decipher the activation states of pDC across tissues and pathophysiological conditions, including in models of viral infections and of type I interferon-driven autoimmune diseases. This will contribute refining our current hypotheses, and generating novel ones, on the physiological functions of pDC. To test these hypotheses, the applicant will use novel mutant mouse models to specifically ablate pDC in vivo constitutively or conditionally, or to inactivate them selectively for the expression of candidate genes, in order to measure how these precise perturbations impact the host immune responses and homeostasis at large.
 
 

Environment

The team of Marc Dalod has made major contributions in the identification and functional study of mouse and human dendritic cell types (http://www.ciml.univ-mrs.fr/science/lab-marc-dalod/experts), including participating to the discovery of mouse pDC1,2 and pioneering the use of comparative genomics to align immune cell types and activation states across tissues and species3-6. The team is structured into three groups each headed by a senior tenure researcher and focusing on a specific research thematic. Dr. Elena Tomasello is directing the research on pDC functions and how they shape the responses of other immune cells including innate lymphoid cells7-9 (and submitted paper; unpublished data). Dr. Karine Crozat is directing the research on mouse professional cross-presenting conventional dendritic cells, XCR1+ cDC1s10,11. Dr. Thien-Phong Vu Manh is leading functional genomics studies, in collaboration with the two other groups and also through the development of original bioinformatics tools and analysis pipelines12,13. Our Institute, the CIML, is currently composed of 14 research groups (http://www.ciml.univ-mrs.fr/science), 6 scientific core facilities (http://www.ciml.univ-mrs.fr/technology), as well as administration and technical services. The CIML is located on the Luminy campus regrouping fundamental research laboratories in all disciplines of life sciences, in informatics, physics, chemistry and mathematics, and biotech start-up companies, including several that emerged from CIML work: Immunotech, Innate Pharma, Oz Bioscience and HalioDx. The team of Marc Dalod also belongs to an Excellency Laboratory focusing on dendritic cell biology (DC-BIOL Labex) headed by Sebastian Amigorena (Curie) and Bernard Malissen (Marseille), as well as to the CenTuri Institut Convergence (http://centuri-livingsystems.org/) which aims at fostering tight collaborations between biologists, mathematicians, physicists and bio-informaticians to understand how biological function emerges from the organization and dynamics of living systems. The applicant will thus benefit from strong collaborations with other teams.
 
 

Applicant profile

The applicant must have a Ph.D. in Immunology or Molecular Biology, a documented positive experience in studying biological functions in vivo in mice, and master either generation of cDNA libraries and qRT-PCR results from low input material or high content flow cytometry data generation and analysis. Advanced expertise in confocal microscopy would be strongly appreciated. Excellent communication skills and team spirit are essential.
 

Social security and retirement included.

Less than 2 years of public employment in France, not taking PhD training into account.

Pre-selection based on written appliaction files.

Shortlising of best appliactions for oral interviews at CIML.

Final selection based on outcome of oral interviews.

References

1. Asselin-Paturel, C, Boonstra, A, Dalod, M, Durand, I, Yessaad, N, Dezutter-Dambuyant, C, Vicari, A, O'Garra, A, Biron, C, Briere, F, Trinchieri, G. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol. 2001;2:1144-1150.

2. Dalod, M, Salazar-Mather, TP, Malmgaard, L, Lewis, C, Asselin-Paturel, C, Briere, F, Trinchieri, G, Biron, CA. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med. 2002;195:517-528.

3. Robbins, SH, Walzer, T, Dembele, D, Thibault, C, Defays, A, Bessou, G, Xu, H, Vivier, E, Sellars, M, Pierre, P, Sharp, FR, Chan, S, Kastner, P, Dalod, M. Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol. 2008;9:R17.

4. Crozat, K, Tamoutounour, S, Vu Manh, TP, Fossum, E, Luche, H, Ardouin, L, Guilliams, M, Azukizawa, H, Bogen, B, Malissen, B, Henri, S, Dalod, M. Cutting edge: expression of XCR1 defines mouse lymphoid-tissue resident and migratory dendritic cells of the CD8alpha+ type. J Immunol. 2011;187:4411-4415.

5. Manh, TP, Alexandre, Y, Baranek, T, Crozat, K, Dalod, M. Plasmacytoid, conventional, and monocyte-derived dendritic cells undergo a profound and convergent genetic reprogramming during their maturation. Eur J Immunol. 2013;43:1706-1715.

6. Ardouin, L, Luche, H, Chelbi, R, Carpentier, S, Shawket, A, Montanana Sanchis, F, Santa Maria, C, Grenot, P, Alexandre, Y, Gregoire, C, Fries, A, Vu Manh, TP, Tamoutounour, S, Crozat, K, Tomasello, E, Jorquera, A, Fossum, E, Bogen, B, Azukizawa, H, Bajenoff, M, Henri, S, Dalod, M, Malissen, B. Broad and Largely Concordant Molecular Changes Characterize Tolerogenic and Immunogenic Dendritic Cell Maturation in Thymus and Periphery. Immunity. 2016;45:305-318.

7. Tomasello, E, Pollet, E, Vu Manh, TP, Uze, G, Dalod, M. Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types. Front Immunol. 2014;5:526.

8. Luci, C, Reynders, A, Ivanov, II, Cognet, C, Chiche, L, Chasson, L, Hardwigsen, J, Anguiano, E, Banchereau, J, Chaussabel, D, Dalod, M, Littman, DR, Vivier, E, Tomasello, E. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol. 2009;10:75-82.

9. Reynders, A, Yessaad, N, Vu Manh, TP, Dalod, M, Fenis, A, Aubry, C, Nikitas, G, Escaliere, B, Renauld, JC, Dussurget, O, Cossart, P, Lecuit, M, Vivier, E, Tomasello, E. Identity, regulation and in vivo function of gut NKp46+RORgammat+ and NKp46+RORgammat- lymphoid cells. EMBO J. 2011;30:2934-2947.

10. Crozat, K, Guiton, R, Contreras, V, Feuillet, V, Dutertre, CA, Ventre, E, Vu Manh, TP, Baranek, T, Storset, AK, Marvel, J, Boudinot, P, Hosmalin, A, Schwartz-Cornil, I, Dalod, M. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207:1283-1292.

11. Alexandre, YO, Ghilas, S, Sanchez, C, Le Bon, A, Crozat, K, Dalod, M. XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses. J Exp Med. 2016;213:75-92.

12. Spinelli, L, Carpentier, S, Montanana Sanchis, F, Dalod, M, Vu Manh, TP. BubbleGUM: automatic extraction of phenotype molecular signatures and comprehensive visualization of multiple Gene Set Enrichment Analyses. BMC Genomics. 2015;16:814.

13. Vu Manh, TP, Dalod, M. Characterization of Dendritic Cell Subsets Through Gene Expression Analysis. Methods Mol Biol. 2016;1423:211-243.