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

Publié dans: J Exp Med 2022 Feb; 219(2):

Auteurs: Nicolas P, Ollier J, Mori D, Voisinne G, Celis-Gutierrez J, Gregoire C, Perroteau J, Vivien R, Camus M, Burlet-Schiltz O, Gonzalez de Peredo A, Clémenceau B, Roncagalli R, Vié H, Malissen B

Résumé

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.

Lien vers Pubmed [PMID] – 35061003

Lien vers HAL – inserm-03554390

Lien vers le DOI – 10.1084/jem.20211295