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Seminar

Wednesday, 3rd, June 2020
10h30
Centre de recherche - Paris - Visioconférence via Zoom

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.

 

 

Speaker(s)

Bernard Malissen
Team leader at, INSERM, CNRS UMR, 13288 Marseille, France

Centre d’Immunologie de Marseille-Luminy and Centre d’Immunophénomique, Aix Marseille Universite

Invited by

Olivier Lantz

Institut Curie

Contact

Sylvia Trival

Send an e-mail

To sum up

Bernard Malissen is the Founder and Director of Centre for Immunophenomics and team leader at Centre d'Immunologie de Marseille Luminy (CIML). He has directed CIML from 1955 to 2005. He is a member of the French Academy of Sciences, an Honorary Member of the American Association of Immunologists and a Fellow of the European Research Council. After receiving his training in Immunology at CIML under the supervision of Claude Mawas and François Kourilsky, he spent two years as a Visiting Associate in the laboratory of Leroy Hood at the California Institute of Technology (Caltech), an then became a team leader at CIML. He pioneered in the eighties the use of gene transfer approaches to dissect the function of molecules involved in T cell function (MHC and TCR). His recent interests aextend to dendritic cells and macrophages, a research area where he disentangled the functional complexity of the dendritic cells found in tissue parenchymas. In the late eighties, the possibility to edit the mouse genome “à la carte” led him to develop innovative mouse models allowing to tackle the function of T cells and dendritic cells in their physiological context. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation, he his presently combining high-throughput “omic” approaches that simultaneously measure large numbers of parameters and genetic screens designed to further the understanding of T cell function under normal and pathological conditions. His laboratory has trained 53 Postdocs, 43 PhD students and 24 Master Students. He published 373 scientific papers and has an h-factor of 90. He also promoted and conducted the construction of the new CIML building ("CIML 2000"; 5000 m2), of the CIML and inter-IFR mouse houses (2000 m2) and of CIPHE (4000 m2).