Quantitative interactomics of the TCR signal-transduction network helps designing coinhibitory-based immunotherapy
The activation of T cells by the T cell antigen receptor (TCR) results in the formation of signaling protein complexes (signalosomes), the composition of which has not been analyzed at system-level. We isolated primary T cells from 17 gene-targeted mice each expressing at physiological levels one tagged-form of a canonical component of the TCR signaling pathway. By analyzing them before and at various times after TCR engagement using affinity purification coupled with mass-spectrometry, we showed that the TCR signal transduction network is far more complex than expected. TCR signals divide extensively at the level of the plasma membrane, leading to the formation of multiple signalosomes that assemble with kinetics and in numbers comparable to the canonical signalosome nucleated by the LAT adaptor. TCR signals are further modulated by coinhibitory receptors and understanding the mode of action of coinhibitory receptors is of fundamental and clinical interest. Using the PD-1 and BTLA coinhibitors, we will illustrate how the comparison of their signalosomes via quantitative interactomics in primary T cells permitted to unveil their extent of redundancy and provided a rationale for designing combinations of blocking antibodies in cancer immunotherapy based on undisputed modes of action. Finally, we will discuss how the quantitative and contextual picture of the TCR signal-transduction network resulting from our approach provides a framework for rationalizing the phenotypic effect of genetic variations or drugs, and for charting the redundant routes of signal propagation a T cell might use to bypass a drug-targeted component, which both constitute central issues in immune system biology.
Team leader at, INSERM, CNRS UMR, 13288 Marseille, France
Centre dImmunologie de Marseille-Luminy and Centre dImmunophénomique, Aix Marseille Universite