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

Project description

Molecular insight into T-cell homeostasis

Under physiological conditions, the T-cell compartment remains stable in terms of composition, indicating the presence of homeostatic mechanisms that regulate cell differentiation, survival and death. Characterising these mechanisms is important for understanding how the immune system functions in health and disease. Funded by the Marie Skłodowska-Curie Actions programme, the COR1-TCELL project will focus on the protein coronin 1, recently shown to be involved in T-cell balance. Using various laboratory techniques and genetic modification, researchers will dissect the molecular pathway of coronin 1. COR1-TCELL’s results will expand our understanding of T-cell regulation, offering potential insights into new therapeutic strategies including the design of CHIMERIC antigen receptor (CAR) T-cell immunotherapy.

Objective

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.

Coordinator

UNIVERSITAT BASEL
Net EU contribution
€ 175 419,60
Address
PETERSPLATZ 1
4051 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 175 419,60