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Centre d'Immunologie et des Maladies Infectieuses
UPMC UMRS CR7 - Inserm U1135 - CNRS ERL 8255

Treg Biology and Therapy - Benoit SALOMON

Team members

Team Research program

Foxp3+CD4+ regulatory T cells (Tregs) play major roles in the homeostasis of the immune system and in the prevention of auto-immune and inflammatory diseases. The overall aim of our project is to increase our understanding of Treg biology in mice to propose innovative treatments in humans. Specific aims of the project will be to address (i) the rules governing the establishment of the Treg pool during ontogeny, (ii) the implications of CD122/MAPK, TNF/NF-Kb and metabolic signaling pathways on Treg biology in physiological and pathological contexts, and (iii) the role played by ICOS/LICOS interaction in anti-tumoral immune responses. The pre-clinical and clinical translation of our results may improve treatments of AID and cancers and vaccine efficacy.
Treg biology in physiological contexts. Based on our data, mouse models and expertise, we will address the following questions; (i) what are the mechanisms behind colonization of the bone marrow and intestine by Tregs during ontogeny ? This question will be addressed using RAG-GFP transgenic mice to trace recent thymic emigrants; (ii) what is the role of STAT-5-independent IL-2-mediated signal in Treg biology? (iii) and what is the role of TNF/NF-kB signaling pathway in Treg homeostasis? These last 2 questions will be addressed using CRE/lox mice that have specific knock-out of the Shc adapter, the type 2 receptor of TNF (TNFR2) and members of the NF-kB signaling pathway (RelA and RelB) in Tregs.
Treg biology in pathological contexts. Treg suppression of autoimmune diseases takes place in an inflamed environment. It is thus critical to analyze the impact of inflammation on their biology. Our work revealed that TNF released during inflammation promotes Treg expansion and suppressive activity. We will address the role of the TNF-mediated NF-kB signaling pathway in the inflamed central nervous system in a mouse model of multiple sclerosis using mice described above (specific knock-out in Tregs of TNFR2 and NF-kB members). In tumors, Tregs express high level of the ICOS costimulatory molecule that may favor their expansion and suppressive activity. We will address the role of ICOS expressed by Tregs during anti-tumoral immune responses using mice with specific knock-out of ICOS in Tregs and in humanized mice.
Innovative therapies involving Treg. The Treg subset expressing ICOS has been described as highly suppressive and ICOS may play an important role in Treg survival and proliferation. A monoclonal antibody against human ICOS will be assessed for its ability to decrease Treg numbers and thus, to improve anti-tumoral immune response in mice bearing a human immune system and human breast tumors. Also, some adjuvants present in vaccines may boost Treg expansion that may limit their efficacy. We will define which adjuvants induce this boost and by which mechanisms, emphasizing on the roles of TNF and NF-kB. This study will help to optimize vaccine composition to improve their efficacy. Following our preclinical mouse studies, we are also involved in a pending clinical trial consisting in injecting pre-activated polyclonal Tregs in the eyes of patients that have severe uveitis.

Technical expertise

  • Mutiparameter flow cytometry
  • Mouse models of type 1 diabetes, multiple sclerosis, IBD and uveitis
  • Humanized mice
  • Lentiviral vectors
  • Purification, culture, expansion, function of mouse and human Treg.

Main achievements

  • Therapeutic effect of low dose IL-2 in autoimmunity by boosting Tregs
  • Treg cell therapy in uveitis
  • Characterization of the TNF effect on expansion and on suppressive activity of Treg in inflamed target tissues
  • Stimulatory effect on Tregs by inducing TNFR2 receptor in mouse modesl for Multiple Sclerose

External funding (current)

At academic level:

  • INSERM Transfert (2014-2016) : Role of the BTLA co-inhibitory molecule in Treg homeostasis
  • AFM (2014-2015) : Genetic addressing of dendritic cells to the thymus for tolerance induction
  • ARSEP (2013-2014) : Role of TNFR2 expressed by Treg in the pathysiopathology of multiple sclerosis in mice.

From industry:

  • GSK (2014-2016) : Targeting ICOS for cancer immunotherapy
  • GSK (2012-2016) : Identification, mechanism and therapeutic implications of Treg activation by immune adjuvants.

Publications (PDF):

(2017 - 2016 - 2015 - 2014 - 2013)

23/10/17

Traductions :

Contact

cimi-paris @ upmc.fr

To see

Key words

Regulatory T cells; T cell homeostasis; Tolerance; Autoimmune diseases; Cancers; Immunotherapy; TNF, ICOS, IL-2, NF-kB, metabolism

Fields of application

Autoimmune diseases, Cancers, Immunotherapies