Final Report Summary - THEMIS (Role of Themis1, a new T cell signaling protein, innormal and pathological immune responses)
A critical component of the immunological response to foreign protein is the activation of T lymphocytes. T-cell receptor (TCR) recognition of peptide loaded-histocompatibility molecules (MHC) provides antigen specificity and initiates the required steps for T-cell activation and differentiation into T cell subsets with specific and adapted immune function. The recognition of peptide-MHC complexes by TCRs triggers the activation of a complex network of intracellular signalling pathways. The quality, the duration and the strength of these signals determine the outcome of T cell responses and is therefore critical for 1) the discrimination between self and non self antigens, 2) the generation and expansion of the appropriate functional T cell subsets, 3) the control of pathological disorders. Understanding T cell signaling constitutes a major challenge to determine the etiology of human pathologies and to facilitate the development of specific therapy. My objectives are to study the molecular aspects of these signaling events and their influences on physiological or pathological immune responses. Before obtaining the CIG grant from the European commission, I was granted of a French national subvention (named ATIP-AVENIR) that allowed me to create a team in a French institute name “Centre de Physiopathologie de Toulouse Purpan” (http://www.cptp.inserm.fr/16762008/0/fiche___pagelibre/&RH=1303811796089). Our experimental approach is to use genetically modified mice deficient (knock-out) for signaling molecules to analyze the molecular mechanism of T cell responses. We recently discovered a signaling protein that we named THEMIS. We generated THEMIS deficient mice and found that this protein plays a critical role during T cell development. On a molecular basis, Themis remained however poorly understood. During the past two years, we described the ability of THEMIS to stabilize the adaptor protein Grb2 and thereby to enhance TCR signaling during positive selection (Zvezdova et al., Science signaling, 2016). We also collaborated to two studies published in Nature Immunology, one that reports the essential role for THEMIS2 in the development of B cells (Cheng et al., Nature Immunology 2016) and one that describes the role for THEMIS CABIT domains in the inhibition of SHPs phosphatase activity (Choi et al, Nature Immunology 2017). We recently submitted a study showing that THEMIS expression level is tightly regulated by ubiquitin-specific proteases during T cell development (Garreau et al., 2017). Our team is now developing two lines of investigation that arose from our past research on THEMIS. This protein has recently been pointed out as a susceptibility factor in multiple sclerosis (MS) and inflammatory bowel disease (IBD) but its precise role in the emergence of these pathologies remains unknown. We have developed a new mice model that will allow us to study the how THEMIS affects the emergence and the severity of these pathologies. In addition, our research on THEMIS led us to begin an investigation on a second protein, Lis1, which has been mostly described for its role in neuronal migration. Preliminary data indicate that this protein is critical for T cell development. Since obtaining the CIG, I was granted of a tenure position and was recruited as assistant professor (CR1) at INSERM in October 2013. I trained several master students (4 M1R, 3 M2R) and supervised the work of 2 technicians/engineers and 2 post-doctoral fellows. Since 2012, 1 PhD was granted under my supervision and 2 are in progress.