PROJET MI-RIOT 5

Ce projet est porté par le centre d’immunophénomique (AMU-INSERM-CNRS) et le CIML

CONTEXT & OBJECTIVES 

Quantitative interactomics of the TCR signal- transduction network of primary effector T cells helps design coinhibitory and costimulatory-based immunotherapies.

T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) information.

Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatments for metastatic melanoma.

However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways.

“À travers cette convention de mécénat, MSDAVENIR nous a permis de réunir la « dream team » dont nous rêvions tant et ce afin d’appliquer à une question d’importance fondamentale et clinique, les outils les plus avancés de la génétique fonctionnelle et de la protéomique.“

Bernard MALISSEN
Directeur du CIPHE, Responsable d’Equipe au Ciml.

RESULTS & PERSPECTIVES

To make sense of the formidable complexity of the signal trans- duction networks involved in T cell activation, we combined “omic” and gene editing.

It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the signalosomes that assemble in primary T cells following physiologic TCR engagement.

We also applied the same strategy to several coinhibitors (CD5, PD-1, BTLA, TIM3) and costimulators (CD6, CD28).

As illustrated here we validated the strategy in the case of the LAT adaptor and then showed that in the case of CD6 and CD5, our systems-level study provides the most comprehensive analysis yet on the composition of the CD6 and CD5 signalosomes of primary effector CD4+ T cells. Interestingly, CD6 assembles in effector T cells a multitask signalosome endowed with both opposite regulatory functions.

The molecular foundation provided for CD6 functions provides cues for future translational applications in settings such as those that lead to autoimmune diseases.

PUBLICATIONS

1. He, L., et al (2021). ARHGAP45 controls naive T- and B-cell entry into lymph nodes and T-cell progenitor thymus seeding. EMBO Rep 22, e52196.

2. Locard-Paulet, et al (2020). LymphoAtlas: a dynamic and integrated phosphoproteomic resource of TCR signalling in primary T cells reveals ITSN2 as a regulator of effector functions. Mol Syst Biol 16, e9524.

3. Mori, D., et al (2021). The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation. J Exp Med 218. e20201011.

4. Zhai, Y., et al (2021). Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics. Cell Mol Immunol 18, 1581-1583.