Objective The immune system maintains a vast repertoire of lymphocytes waiting to respond to microbial invasion. These cells are kept in a quiescent state, characterized by arrest in G0 and a decrease in cell size and metabolic activity, until they are activated. Not long ago, quiescence was considered equivalent to “absence of activation”, namely a default state of the cell. Recently our discovery of a chemically induced mutation, elektra, enabled us to illustrate what happens when quiescence fails. Elektra mice showed an abnormally high frequency of T-cells in a semi-activated state and suffered from immunodeficiency. We ascribed the elektra phenotype to a mutation in Slfn2, a gene of previously unknown function, and concluded that SLFN2 plays an essential role in immune defense, where it operates to maintain quiescence in T-cells and monocytes. Moreover, our results demonstrate that quiescence programming must be actively maintained. However, lymphocyte quiescence is still poorly understood and the mechanism by which SLFN2 maintains it is also unknown. We now propose to use molecular approaches combined with unbiased forward genetic screening to elucidate mechanisms by which SLFN2 enforces T-cell quiescence. Specifically, we will: 1) identify SLFN2 binding partners and investigate the nature of the interactions; 2) elucidate key molecular processes in T-cells regulated by SLFN2 by a forward genetic screen. These findings will likely have relevance to other immune cell populations which are not T-cells and may also clarify the function of other members of the SLFN family. The identification of lymphocyte quiescence maintaining factors will integrate to understand how the immune system is able to defend the host while maintaining self tolerance and therefore have the potential to be exploited for therapeutic purposes in immune disorders, either by enhancing specific anti-pathogen/tumor immune responses or by suppressing overactive, self-directed responses. Fields of science medical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesgeneticsmutation Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Call for proposal FP7-PEOPLE-2012-CIG See other projects for this call Funding Scheme MC-CIG - Support for training and career development of researcher (CIG) Coordinator THE HEBREW UNIVERSITY OF JERUSALEM EU contribution € 100 000,00 Address EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Israel See on map Activity type Higher or Secondary Education Establishments Administrative Contact Hani Ben Yehuda (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
