Jean-Pierre DE VILLARTAY et Patrick REVY

Genome dynamics in the immune system

The immune system is the site of important genetic dynamics generated by specific molecular mechanisms: V(D)J recombination, Ig isotypic class switching (CSR), and generation of somatic hypermutations (SHM). In addition, the cell proliferation and activation phases that take place during lymphocyte maturation or during immune responses are also prone to DNA lesions, which can be qualified as "environmental” damage. Lastly, proliferating immune cells also rely on a tight control of their telomere integrity.

Proficient DNA repair machinery is therefore needed not only to ensure proper T and B cell development but probably also for harmonious lymphocyte homeostasis in the periphery. Our group (which has a longstanding interest in studying general DNA repair processes in the immune system) has identified two of the seven factors involved in the non-homologous end joining (NHEJ) DNA repair pathway: Artemis and Cernunnos. The goals of our research projects are to analyze DNA repair processes and telomere physiology in the context of the immune system.

Our projects are based on dual approaches :

• The functional analysis of DNA repair and telomere physiology by surveying human diseases.
• The development of specific animal models to gain an overview of the genetic dynamics in various aspects of the immune system.

To address these questions, we benefit from the unique recruitment potential for SCID patients at Necker Hospital and the design of new conditional KO animal models. The development of these animal models is of critical importance when studying the role of DNA repair factors in mature lymphocytes, such as during the process of immunoglobulin class switch recombination (CSR).