THEMIS · Role of Themis1, a new T cell signaling protein, in normal and pathological immune responses

A critical step of an immunological response is the activation of T lymphocytes through intracellular signaling pathways downstream of T cell receptors (TCR). THEMIS1 is a new actor of T cell signaling that belongs to a newly identified family of proteins. THEMIS proteins each contain a previously uncharacterized globular domain (called 'CABIT') whose structure and function are currently unknown. We generated THEMIS1 knockout mice and show that this protein is essential for developing T cells in the thymus. THEMIS1 is also express in CD4+ and CD8+ peripheral T cells. Since very few T cells egress to peripheral organs in THEMIS1 knockout mice, little is known about this protein during immune responses. THEMIS1 has recently been pointed out as a susceptibility factor in Celiac disease and Multiple sclerosis, and recent study in rats also revealed that THEMIS1 deficiency leads to the development of spontaneous inflammatory bowel disease. Whether this results directly from THEMIS1 deficiency in T cells or is a secondary effect due to the decrease numbers of T cells in lymphoid organs (lymphopenia) needs to be resolved. The objective of the present proposal is: 1) to perform a structural and functional analysis of THEMIS1 CABIT domains and to establish THEMIS1 interactome in T cells, 2) to determine the physiological and cellular role of Themis in peripheral T cells, 3) to study the contribution of Themis on the development of autoimmune and inflammatory diseases using experimental murine models. I discovered THEMIS proteins during my post-doctoral research at the National Institutes of Health (Bethesda, USA) and I have recently established a lab in France (sponsored by the French government) to pursue our researches on this new family of molecules. Additional supports are now essential to fully develop our projects that we believe could lead to major findings in structural biology, immunology and immunopathology.