The role of the nucleotide-gated cation channels P2X7 and TRPM2 for TCR signalling

• Applicants: Professor Dr. Andreas H. Guse; Professor Dr. Friedrich Haag
• Subject Area: Biochemistry ; Immunology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263128973

P2X7 and TRPM2 are cation channels expressed by T lymphocytes that are gated by extra- and intracellular adenine nucleotides, respectively. Although increasing evidence points to a pivotal role of both channels in inflammation, their effects on T cells remain unclear. The primary goal of the current project is thus to characterize the roles of P2X7 and TRPM2 during the early events of T cell activation. To this end, we will use live cell Ca2+ and ATP imaging, HPLC, and patch-clamp techniques to study the roles of these channels in TCR signaling. Especially, we will test the hypothesis that 2-deoxy-adenosine diphosphoribose (2-deoxy-ADPR), instead of ADPR, is the major endogenous activating ligand of TRPM2. Further, we will characterize TCR- and P2X7-induced release of ATP, its localization in relation to the immunological synapse, and its relevance for T-cell activation, thereby providing a link between the worlds of signaling by intra- and extracellular nucleotides. Characterization of the roles of P2X7 and TRPM2 in TCR signaling will provide the basis for assessing the potential of new therapeutic strategies aimed at targeting these two ion channels.

• DFG Programme: Research Grants