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Journal Articles Journal of Experimental Medicine Year : 2022

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

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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 systemslevel 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.
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Dates and versions

inserm-03554390 , version 1 (03-02-2022)

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Philippe Nicolas, Jocelyn Ollier, Daiki Mori, Guillaume Voisinne, Javier Celis-Gutierrez, et al.. Systems-level conservation of the proximal TCR signaling network of mice and humans. Journal of Experimental Medicine, 2022, 219 (2), pp.e20211295. ⟨10.1084/jem.20211295⟩. ⟨inserm-03554390⟩
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