Investigating the role of retrograde transport in T lymphocyte activation – RETROTACT

T lymphocytes perceive and respond to their environment by engaging receptors and transmitting intracellular messages through signal transduction cascades. This process is controlled by networks of proteins that bind to each other, dissociate, forming multiple signalosomes, which advance signal progression along biochemical pathways. It is this modular interconnectivity between proteins and pathways that is responsible for converting multiple signaling inputs in discrete cellular responses. Our hypothesis is that the localization of signalosomes in T lymphocytes — at the plasma membrane and on internal organelles — has a key role in regulating these circuits. The role of such subcellular compartmentalization in the formation of signalosomes in lymphocytes is indeed still very little explored. In pioneering sudies we showed that the intracellular trafficking of LAT, a scaffolding transmembrane molecule involved in signalosome formation and TCR triggering, is regulated by, and involved in T cell activation. Very recently, the 3 partners of the present proposal discovered that LAT follows the canonical retrograde pathway from the plasma membrane to the Golgi. Of note, it turned out that this retrograde trafficking was required for LAT localization to the immunological synapse, likely due to the polarized secretion of LAT that had reached the Golgi by retrograde transport to this specialized plasma membrane site. The objectives of this project are to study whether signalosomes that were built at the plasma membrane undergo retrograde transport, and whether they then locally signal in the Golgi. Furthermore, using a vectorial proteomic approach, we will establish the full retrograde proteomes of resting versus activated T cells, and characterize, in a mouse model, the in vivo effects of inhibition of the retrograde pathway on T cell functions. By combining cell biology, biochemistry, and chemical biology in primary human T cells and mouse models, we expect to obtain an integrated view on the role of the retrograde transport in the activation of T cells. Since dysfunctional retrograde transport has been implicated in many pathologies (neurodegenerative diseases, viral infections by HIV-1 or the herpesvirus Saïmiri…), this study shall identify targets for therapeutic intervention in a number of disease indications, and contribute to a better understanding of these pathologies.