Analysis of the role for coronin 1-dependent cell density signalling in T-cell homeostasis

Description du projet

Aperçu moléculaire de l’homéostasie des lymphocytes T

Dans un contexte physiologique, la composition du compartiment des lymphocytes T reste stable, ce qui témoigne de la présence de mécanismes homéostatiques qui régulent la différenciation, la survie et la mort des cellules. La caractérisation de ces mécanismes est essentielle à la compréhension du fonctionnement du système immunitaire des individus en bonne santé et malades. Financé par le programme Actions Marie Skłodowska-Curie, le projet COR1-TCELL se concentrera sur la protéine coronine 1, dont l’implication dans l’équilibre des lymphocytes T a été récemment démontrée. Les chercheurs disséqueront la voie moléculaire de la coronine 1 à l’aide de diverses techniques de laboratoire et de modifications génétiques. Les résultats de COR1-TCELL élargiront notre compréhension de la régulation des lymphocytes T, ouvrant de potentielles perspectives pour de nouvelles stratégies thérapeutiques, dont notamment la conception d’une immunothérapie par lymphocytes T à récepteur antigénique chimérique (CAR en anglais).

Objectif

Harnessing T-cell homeostasis is important for cancer immunotherapy as well as anti-microbial immunity and the prevention of autoimmune disorders. T-cell homeostasis in peripheral lymphoid organs is known to be regulated through interleukin-7-mediated cytokine signalling and via T-cell receptors recognising self-peptides loaded on major histocompatibility complex. However, recent results suggest a requirement of a third pathway at low T-cell density such as in newborns that depends on the WD repeat protein family member coronin 1, the mechanism of which is unknown. The objective of this proposal is to elucidate the molecular mechanism of coronin 1-dependent sensing of low cell density that contributes to peripheral T-cell homeostasis.
In preliminary work, I established a co-culture assay of T cells and antigen presenting cells that recapitulates coronin 1-dependent T-cell survival at low cell density. In addition, I found that adoptive transfer experiments reconstituted the coronin 1-dependent peripheral T-cell expansion in a lymphopenic environment in vivo. To delineate the molecular mechanisms underlying this cell density-dependent signalling mediated by coronin 1, I will combine the originally established in vitro and in vivo assay systems with state-of-the-art single-cell RNA sequencing, in addition to biochemical analysis utilising mass spectrometry. This will identify the signalling pathways and the molecules involved in this density-sensing mechanism. Finally, ad-hoc ablation of coronin 1 using a newly established inducible knockout mouse will reveal the role for coronin 1 in the maintenance of peripheral T cells after successful expansion at post-neonatal stage.
The results from this project will define a hitherto uncharacterized density-sensing pathway required for T-cell homeostasis. Furthermore, the fellowship will potentiate my career opportunities as it allows to explore cutting-edge biology and technologies in a highly stimulating research environment.