Objective Although the T cell antigen receptor (TCR) occupies a central place in T cell physiology, it does not work in isolation and the signals it triggers are tuned by receptors that convey positive (costimulators) and negative (coinhibitors) informations. We lack a satisfying comprehension of the way T cells integrate such multiple inputs to make informed decisions. The proteomics-based methodology we developed around the TCR places us in a favorable situation to decode at systems-level the crosstalk between the TCR, the CD28 costimulator and the PD-1 coinhibitor signaling pathways. The novelty of our approach stems from (1) its use of primary T cells, (2) its capacity to probe the architecture and dynamics of signalosomes resulting from T cell-antigen presenting cell encounters, (3) the attention we pay to the stoichiometry of the studied signalosomes, a key parameter largely ignored in previous studies, and (4) its multidisciplinary nature straddling molecular and organismal scales.Our specific aims are:Aim 1. To understand how the TCR and CD28 signaling pathways cooperate to achieve optimal T cell responses. Aim 2. To determine whether CD28 is the sole target of the PD-1 coinhibitor.Aim 3. To determine how under inflammatory conditions CD28 functions can be superseded by those of OX40, a costimulator of the TNFR superfamily.Aim 4. To unveil how malfunctions of LAT, a key signaling hub used by the TCR, disrupt the TCR-CD28 crosstalk and result in unique pathogenic T cells that by becoming ‘autistic’ to TCR signals and addicted to CD28 signals lead to severe immunopathologies.We think that combining genetic, epigenomics, proteomics, and computational approaches creates ideal experimental conditions to understand at system-levels how TCR, costimulatory, coinhibitory and inflammatory signals are integrated during T cell clonal expansion. Although of fundamental nature, our project should help understanding the harmful role PD-1 plays during anti-tumoral responses. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicinephysiologynatural sciencesbiological sciencesgeneticsepigenetics Keywords Lymphoproliferative disorders Integrative biology Proteomics Gene editing Single cell transcriptomics Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2017-ADG - ERC Advanced Grant Call for proposal ERC-2017-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS Net EU contribution € 2 000 000,00 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 000 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS France Net EU contribution € 2 000 000,00 Address RUE MICHEL ANGE 3 75794 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 000 000,00
