The proposed thesis topic is dedicated to the study of CD8 innate T lymphocytes (LTI), a cellular population of natural immunity whose princeps description in humans was provided by the immunology laboratory IRATI (for “ImmunoRegulation, Alarmines and Innate T cells”) headed by André Herbelin (DR INSERM) within the UMR IRMETIST U1313.
Subject: Our data, together with those from the literature, suggest that CD8 LTI harbor both effector and regulatory functions in normal (tumour and infectious immune surveillance) and pathological (autoimmunity, organ transplant graft tolerance) situations. The goal of the proposed research program is to achieve a comprehensive characterization of this heterogeneous cell pool that we initially described based on KIR (human)/Ly-49 (mouse) and/or NKG2A receptor expression. This global KIR/NKG2A phenotype is associated with the expression of the transcription factors Eomes, T-bet, and Helios, as well as with innate-like regulatory functions, the acquisition of which we presume is initiated during central differentiation by selection by self-antigens. We will test the assumption that CD8 LTI contain two distinct contingents: (i) an NKG2A effector pool Eomes(+)/T-bet(+) producing IFN-g and (ii) a regulatory KIR pool Helios(+) with suppressive (cytotoxic/anti-proliferative) functions.
This first part of the project will be based on the analysis of LTI CD8 (NKG2A versus KIR) at steady-state in human placental blood as well as in the central (thymus) and peripheral (spleen and ganglia) organs of the mouse. We assume that CD8 KIR LTI have a role in organ transplant graft tolerance, hence the proposed research program also has a medical focus. We will perform a comprehensive monitoring of CD8 LTI (NKG2A versus KIR) from peripheral blood of renal transplant patients from our local cohort, including analyzing their specific antigen versus bystander response to donor antigens. The CD8 LTI profiles obtained will be crossed with clinical criteria to determine their possible association with graft tolerance. The PhD student will be associated with this translational part, for which the referent is Pr. Antoine Thierry (responsible for renal transplantation in the nephrology department of the CHU de Poitiers), co-supervisor of the thesis.
Ultimately, our project should contribute to a better knowledge of biology of innate CD8 LTI by aiming at new knowledge of the immune mechanisms involved in tolerance with the medical goal of being able to propose a minimized immunosuppression to transplant patients bearing an immune tolerance signature of the graft.
Methods: To carry out this project, we will use the highly resolutive spectral flow cytometry technic to refine our understanding of the compartmentalization of innate CD8 LTI (NKG2A(+) versus KIR(+)/Ly-49(+). Primary cell culture and co-culture techniques will be required, as well as stimulation and sorting of cells by flow cytometry. The PhD candidate will receive extensive training in multi-parameter data analysis (supervised and unsupervised analysis).
About the lab: The laboratory Ischémie Reperfusion, Métabolisme et Inflammation Stérile en Transplantation (IRMETIST) is a joint INSERM/Université de Poitiers research unit (U1313). The unit is an integral part of the Federal Research Institute (IFR) for Biohealth (BioSanté). It is located in Poitiers, a city at human size between Paris and Bordeaux, each at 1h30 by train. The unit is located partly on the site of the Poitiers CHU near the Faculty of Medicine and Pharmacy and partly at the health biology pole (PBS) on the campus of the University of Poitiers. The PhD student will be located on the PBS site and will benefit from a stimulating environment close to the other IFR BioSanté laboratories, with privileged access to campus platforms.
The research themes of the unit are the improvement of the conditions of organ transplantation and the study of lesion phenomena related to ischemia-reperfusion. In this context, IRATI group is dedicated to applying fundamental and clinical immunology to the development of the unit’s projects. Its main area of activity is the study of innate T cells and IL-33, an alarmin-like cytokine, in normal and pathological situations.
Candidate profile:
- The candidate must have a Master 2 degree in cellular immunology and a good knowledge of both the human and murine immune systems.
- A theoretical and practical knowledge of flow cytometry is desirable.
- The ideal candidate will be motivated, curious, pro-active, independent and rigorous. He/she will join a stimulating, collaborative and engaging environment.
- An animal work is part of the project and therefore the candidate will agree to work with such models. Animal experimentation diploma is needed but can be acquired in the lab.
- Very good spoken and written English is required to communicate in the lab and particularly with the international network of collaborators.
Application: candidate must submit:
- a motivation letter and a resume detailing his university cursus and the relevant professional experience (particularly internship performed during studies)
- grades of his Master degree (1 & 2) as well as the ranks obtained for those years.
- contact information for at least 2 mentors/referents
Contatcs: [email protected]/[email protected]
