T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) primarily controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) informations about the state of activation of antigen-presenting cells (primarily dendritic cells). Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatment for several malignant conditions, leading to a revival in the study of T cell coinhibition and costimulation. However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways and use inter-pathway crosstalk to make informed decisions. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation and the role played by the different types of dendritic cells in T cell activation, we combined “omic” and mouse genetics. It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the protein signaling complexes (signalosomes) that assemble in primary T cells following physiologic TCR engagement. To further illustrate the interest of multi-omics approaches, I will present recent data generated with several Japanese collaborators and demonstrating how corrupted LAT signalosomes lead to an inflammatory and autoimmune disease recapitulating human IgG4-related disease.