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Identification of novel receptors that may substitute the TCR signal in health and disease. Analysis of the mechanisms for activation of alpha-beta and gamma-delta T cells in LAT mutant mice.


The laboratory of B. Malissen has recently constructed knock-in mice displaying various point mutations in the adaptor protein LAT, which developed pathologies reminiscent of that of asthmatic patients developing exacerbated Th2 responses and of patients s uffering of idiopathic hypereosinophilic syndrome. One model showed early accumulation of polyclonal helper T cells that chronically produce type 2 cytokines in large amounts. In a second model, alpha-beta T cell development was blocked, but later gamma-de lta T cells accumulated in the spleen and lymph nodes and chronically produced large amounts of T helper type 2 cytokines.In both models the TCR module appears largely non-functional in that it can not elicit signals following engagement with a cognate lig and. Based on these results, we reasoned that other mechanisms have to substitute for antigen-specific TCR signals and control the proliferation and survival of these cells. Therefore, the first objective of the present proposal aims at analyzing the cellu lar pathways and signaling mechanisms leading to excessive Th2 lymphoproliferation in the LAT mutant mice using genetics and RNA profiling. The second objective of the proposal attempts at understanding the mechanisms controlling the activation of gamma-de lta T cells in vivo. A novel tagging approach relying on a histone 2B GFP fusion protein will allow both their identification in situ and the monitoring of their cell cycle status. Gamma-delta T cells still constitute a mysterious component of the immune s ystem that is probably involved in the defense against microbial infection and tumors. It is expected that the visualization of the dynamics of gamma-delta T cell proliferation and death in tissues will contribute to the understanding their function. In co nclusion, the present project will further our understanding of the regulation of T cell activation, and, in the long term, pave the way to the rational control of detrimental immune reactions.

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