Systems-level conservation of the proximal TCR signaling network of mice and humans

• Published in: The Journal of experimental medicine Vol. 219; no. 2
• Main Authors: Nicolas, Philippe, Ollier, Jocelyn, Mori, Daiki, Voisinne, Guillaume, Celis-Gutierrez, Javier, Gregoire, Claude, Perroteau, Jeanne, Vivien, Régine, Camus, Mylène, Burlet-Schiltz, Odile, Gonzalez de Peredo, Anne, Clémenceau, Béatrice, Roncagalli, Romain, Vié, Henri, Malissen, Bernard
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.02.2022
• Subjects: Animals; Biomarkers; Cell Communication - immunology; Gene Editing; Humans; Immunology; Immunophenotyping; Life Sciences; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Mice; Models, Biological; Phosphorylation; Protein Interaction Mapping; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Species Specificity; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Technical Advances and Resources
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20211295

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.