Our research explores the autoimmune pathogenesis of type 1 diabetes (T1D) and the discovery of new T-cell-based biomarkers and therapeutic tools, using both human and mouse experimental systems.
Two postdoctoral positions are available on two projects:
- A project entitled "Mechanisms of progression of benign islet autoimmunity toward type 1 diabetes". Our recent work (Culina et al., Science Immunology 2018) documented that islet-reactive CD8+ T cells circulate at similar frequencies in T1D and healthy donors and display a predominantly naïve phenotype, hence they are not actively involved in the autoimmune process. The fraction engaged in the disease is instead sequestered in the pancreas and is found enriched in T1D patients. Thus, a universal state of ‘benign’ autoimmunity exists in all individuals. This project will decipher the mechanisms driving the progression of this benign state toward T1D. Two hypotheses will be considered. First, loss of immune ignorance, by which co-stimulatory and co-inhibitory molecules expressed by islet beta cells in the inflammatory milieu of the T1D pancreas may modulate their own vulnerability. Second, loss of immune regulation, i.e. only the autoreactive T cells of T1D may become resistant to suppression and/or acquire the ability to migrate to the pancreas. We have compared the gene expression profile of autoreactive T cells from T1D and healthy donors and identified some promising pathways that the candidate will explore. The ultimate goal is the discovery of new autoimmune biomarkers and of novel therapeutic targets aimed at reverting T1D autoimmunity back to its benign state. The Postdoc will design and set up experiments for the progression of the project. Candidate genes have already been identified by RNAseq and will be validated with functional assays employing original T-cell/beta-cell co-culture systems and short-term in vitro peptide stimulation combined with HLA tetramers for the activation and detection of CD8+ and CD4+ islet-reactive T cells. He/she will use this information to formulate and test novel hypotheses.
- A project entitled “Identifying T-cell responses against viral epitopes and their potential cross-reactivity with islet autoantigens”. Environmental factors play a dominant role over genetic predisposition in T1D pathogenesis, yet they remain elusive. We will be examining the potential role of viral infections and mechanisms thereof, with a particular focus on the cytotoxic effects directly exerted on beta cells and/or on triggering of autoimmune T cells through viral amino acid sequences sharing homology with beta-cell epitopes. The ultimate goal is to establish whether a causal relationship between viral infections and beta-cell autoimmunity exists, and to gain information to guide the development of preventative vaccines. The Postdoc will design and set up experiments for the progression of the project. Candidate epitopes are identified using mass spectrometry-based peptidomics techniques. He/she will validate these candidates for their (cross)recognition by T cells from T1D and healthy subjects, using different T-cell assays based on flow cytometry, HLA tetramers, T-cell cloning and in vitro functional assays. He/she will use this information to formulate and test novel hypotheses using both T-cell and beta-cell culture systems.
- Knowledge: A strong expertise in multiparametric flow cytometry, cell sorting, cell culture and previous experience in immunology research is preferred. Fluent English, written and spoken. Applications not fulfilling these criteria will not be considered.
- Professional skills: The candidate must be highly motivated and use creative thinking in the resolution of scientific questions. He/she will be able to adapt to rapidly evolving technologies and will have a broad interest for biomedical research. He/she will need to give proof of independent thinking and writing skills and capacity to undertake responsibility as project leader. It is essential that the candidate can work autonomously and as part of a team.
- Education: MD/PhD or PhD in biological sciences.
The DeAR Lab is part of the Team « Immunology of Diabetes » of the Cochin Institute. The Cochin Institute is one of the largest biomedical French Research Center located in the center of Paris that provides a multidisciplinary scientific environment and state-of-the-art core facilities. It is affiliated with the French National Institute for Health and Medical Research (Inserm), the Paris Descartes University, the CNRS and the Assistance Publique/Hôpitaux de Paris. It is associated with the Clinical Department of Diabetology of the Cochin Hospital. It belongs to different international consortia such as the European IMI2 Innodia (www.innodia.eu) and the Network for Pancreatic Organ Donors (nPOD; www.jdrfnpod.org).
We offer a stimulating and productive lab environment of young researchers with strong team spirit. This is an excellent career opportunity, as the candidate will have a senior role within the Laboratory and interact with several international collaborators.
Further information. About our Laboratory: www.dearlab.org; about our institute: www.institutcochin.fr.
Type: Temporary positions
Funding: EU H2020, Juvenile Diabetes Research Foundation
Beginning: July 2018
Duration of contract: 12-month contract renewable for up to 5 years.
HOW TO APPLY?
Applicants should send their CV, list of publications, research summary and the names of two references to Roberto Mallone and Sylvaine You: firstname.lastname@example.org, email@example.com
Representative publications of the Laboratory
- S. Culina*, A.I. Lalanne*, G. Afonso, K. Cerosaletti, S. Pinto, G. Sebastiani, K. Kuranda, L. Nigi, A. Eugster, T. Østerbye, A. Maugein, J.E. McLaren, K. Ladell, E. Larger, J.P. Beressi, A. Lissina, V. Appay, H.W. Davidson, S. Buus, D.A. Price, M. Kuhn, E. Bonifacio, M. Battaglia, S. Caillat-Zucman, F. Dotta, R. Scharfmann, B. Kyewski, R. Mallone, the ImMaDiab Study Group. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetes from healthy donors. Sci Immunol 2018 (cover article).
- Culina S, Gupta N, Boisgard R, Afonso G, Gagnerault MC, Dimitrov J, Østerbye T, Luce, Attias M, Kyewski B, Buus S, Wong FS, Lacroix-Desmazes S, Mallone R. Materno-fetal transfer of preproinsulin through the neonatal Fc receptor prevents autoimmune diabetes. Diabetes 2015.
- Gupta N, Culina S, Meslier Y, Dimitrov J, Arnoult C, Delignat S, Gangadharan B, Lecerf M, Justesen S, Gouilleux-Gruart V, Salomon BL, Scott DW, Kaveri SV, Mallone R, Lacroix-Desmazes S. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Sci Transl Med 2015.
- Scotto M, Afonso G, Østerbye T, Larger E, Luce S, Raverdy C, Novelli G, Bruno G, Gonfroy-Leymarie C, Launay O, Lemonnier FA, Buus S, Carel JC, Boitard C, Mallone R. HLA-B7-restricted islet epitopes are differentially recognized in type 1 diabetic children and adults and form weak peptide-HLA complexes. Diabetes 2012.
- Martinuzzi E, Afonso G, Gagnerault MC, Naselli G, Mittag D, Combadière B, Boitard C, Chaput N, Zitvogel L, Harrison LC, Mallone R. acDCs enhance human antigen-specific T-cell responses. Blood 2011.