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

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. Nicolas et al. exploited traceable gene tagging in primary human T cells to establish at the systems level the composition and dynamics of TCR-induced signalosomes. It provides a decision-support tool accelerating definition of the mechanism of action of drugs targeting T cells.

Automated summary

Using traceable gene tagging, we investigated the composition and dynamics of TCR-induced signalosomes in human T cells. We found a high degree of conservation in the proximal TCR-signaling network between human CD4(+) and CD8(+) T cells, as well as between human and mouse T cells. Our study suggests that drugs targeting the proximal TCR signaling network should behave similarly when applied to human and mouse T cells. However, differences likely exist in the distal TCR-signaling pathway, and our fast-track AP-MS approach can be favored to determine the mechanism of action of drugs targeting human T cell activation.