Identifying novel T cell checkpoints via quantitative proteomic of signalosomes in primary T cells
T cells probe the surface of dendritic cells in search of molecular cues reflecting the antigenic and inflammatory status of the body tissues and its malfunction has pathological consequences. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation, we have developed mice that bear a genetic tag that permits purification coupled with mass spectrometry (AP-MS) of T cell signalling proteins with their interaction partners from primary T cells. We showed that among the hundred of proteins that composed the proximal T cell antigen receptor signaling network, a majority has never been identified before. Ten novel lines of gene-targeted mice have been studied providing a comprehensive and fine-grained view of the proximal TCR signaling network. We have combined this high-throughput “omic” approach with genetic screens designed to identify novel components of the CD28 costimulatory pathway. Rather than the tens of components previously thought to compose the TCR and the costimulatory/coinhibitory signal transduc- tion networks, our studies suggest the involvement of hundreds. In view of the grand challenges that exist, humility is a more appropriate reaction than hubris. However, as we will illustrate the prospects of integrating in vitro, in vivo and in silico approaches, each bearing unique advantages and drawbacks, to understand T cell activation and identifying novel checkpoints are excellent.