Systems-level conservation of the proximal TCR signaling network of mice and humans
Philippe Nicolas, Jocelyn Ollier, Daiki Mori, Guillaume Voisinne, Javier Celis‐Gutierrez, Claude Grégoire, Jeanne Perroteau, Régine Vivien, Mylène Camus, Odile Burlet‐Schiltz, Anne Gonzalez de Peredo, Béatrice Clemenceau, Romain Roncagalli, Henri Vié, Bernard MALISSEN
Abstract
We exploited traceable gene tagging in primary human T cells to establish the composition and dynamics of seven canonical TCR-induced protein signaling complexes (signalosomes) using affinity purification coupled with mass spectrometry (AP-MS). It unveiled how the LAT adaptor assembles higher-order molecular condensates and revealed that the proximal TCR-signaling network has a high degree of qualitative and quantitative conservation between human CD4+ and CD8+ T cells. Such systems-level conservation also extended across human and mouse T cells and unexpectedly encompassed protein-protein interaction stoichiometry. Independently of evolutionary considerations, our study suggests that a drug targeting the proximal TCR signaling network should behave similarly when applied to human and mouse T cells. However, considering that signaling differences likely exist between the distal TCR-signaling pathway of human and mouse, our fast-track AP-MS approach should be favored to determine the mechanism of action of drugs targeting human T cell activation. An opportunity is illustrated here using an inhibitor of the LCK protein tyrosine kinase as a proof-of-concept.