Natural Killer (NK) cells are lymphocytes of the innate immune system that recognize and induce the lysis of a variety of target cells, including virally-infected cells, tumor cells, and allogenic cells without prior specific sensitization.
In addition, NK cells elaborate a variety of regulatory cytokines including IFNg, TGFß1, TNFa, IL-1bß, IL-10, G-CSF, and GM-CSF and CC-chemokines, such as RANTES, MIP-1a and MIP-1bß which are involved in the elimination of intracellular pathogens in vivo, as well as in the generation of antigen-specific immune response.
A feature of NK cell cytolytic activities and cytokine production is that their initiation is dependent upon the integrity of MHC class I expression on target cells. Indeed, NK cells express cell surface receptors such as KIR in humans, Ly49 in the mouse, and CD94/NKG2 heterodimers in both species, that can sense the alteration of MHC class I molecules at the surface of target cells.

The main goal of our group is to contribute to the dissection of the functions of NK cells in vivo by elucidating the receptors that confer to NK cell the capacity to distinguish target from non-target cells. We believe that the results obtained in this aim will contribute to reveal novel mode of immune recognition and to precisely envision the potential indications of NK cell manipulation in novel immunotherapeutic strategies.

Another important aspect regarding NK cell physiology is the anatomical distribution of NK cells in the whole organism. NK cells are mainly generated in the bone marrow and can be isolated in the periphery in the spleen, the liver, the lungs, the uterus, the lymph nodes, the thymus, and the peripheral blood. Interestingly, in both humans and mice, the NK cells that are present in different organs harbor distinct phenotypes and functions. Whether NK cells are present in the majority of epithelial tissues is poorly documented and hotly debated. This aspect is of particular interest, as epithelial tissues constitute the first barrier against most microbial, chemical or physical aggressions. We have recently started a new research program focused on the identification and characterization of NK cells in both mouse and human epithelial tissues. Our first goal is to define whether NK cells reside in these tissues under steady-state conditions and/or migrate there under inflammatory conditions. Subsequently, we intend to dissect the role of “epithelial NK cells” in the homeostasis of healthy epithelial tissue as well as in the development of diverse pathologies affecting these tissues.

Self versus non-self discrimination is a central theme in biology, extending from plants to vertebrates. Natural killer (NK) cells in the mammalian immune system constitute an experimental model system for investigating the molecular and cellular mechanisms involved in these complex biological processes. Indeed, NK cells are tolerant to normal self tissues, but kill and produce cytokines in response to cells in distress (tumors, infected cells…). Studies in humans and mice have shown that self-recognition is required for NK cells to acquire functional competence. However, little is known about this developmental process. We therefore propose to elucidate the mechanisms of NK cell "education" to self versus non-self discrimination.

Understanding such complex system, from the molecular scale to higher level tissue architecture and beyond, to the physiology of whole organisms, requires multiple approaches at various levels. We thus work up from the whole organism to the molecular scale. In particular, new mouse mutants are generated by random germline mutagenesis using ENU (N-ethyl-N-nitrosourea). We also try to understand the system as a whole, using genome-wide transcriptome analysis and NK cell imaging in tissues. Finally, the real-time observation of protein dynamics in living cells using a FCS (Fluorescence Correlation Spectroscopy) method in collaboration with the group of D. Marguet (CIML), will allow to measure parameters, such as the number of molecules, diffusion coefficients, spatial distributions and temporal fluctuations, essential for the generation of quantitative models.

By determining the mechanisms allowing both NK cell self-tolerance and their ability to respond to diseased cells, we should improve our understanding of biological processes that may operate broadly in the vertebrate innate immune system. This inter-disciplinary project should also contribute to define the rationale basis of manipulating NK cells in ongoing and forthcoming innovative anti-cancer clinical trials.