Cell tension coordinates cellular processes leading to T cell activation

• Applicant: Dr. Jeremie Rossy
• Subject Area: Immunology ; Biophysics ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436846661

T cells play a central role in the adaptive immune system, either by orchestrating the response of other immune cells in the case of CD4+ helper and regulatory T cells, or by directly removing infected and cancer cells in the case of cytotoxic CD8+ T cells. When scanning for cognate peptides, T cells are polarized and migrate on various substrates and extracellular environments. Adhesion, actin polymerisation at the leading edge and actomyosin contractions in the uropod generate forces and tension in migrating T cells. Similarly, activation by antigen-presenting cells leads to actin retrograde flow within the lamella at the periphery of the IS and contractions generated by actomyosin arcs at the inner edge of the lamella. Although they are produced by the same cellular machinery, forces in migrating cells and during T cell activation have different kinetics and geometry. Thus, the differences in morphology, polarity and adhesion going along with the transition from migration to activation lead to significant changes in cell tension. Increasing evidence shows that gradients of tension can be maintained in cells. Existence of different tensions at different subcellular localisations means that tension can have a signalling function and orchestrate cellular processes. In fact, among other things, tension has been shown to regulate cell shape and polarity, cytoskeletal organisation, exo/endocytosis and even nuclear events.Hence, the working hypothesis of this research project is that these changes in cell tension induce a mechanical coupling that contributes to organise and coordinate changes in signalling and intracellular trafficking taking place upon TCR engagement of a cognate peptide.Abundant evidence shows that force is a key factor in T cell activation. T cells can sense stiffness and the T cell receptor is a mechanosensor. However, a) mechanobiology experiments on T cells rarely reproduce the actual tensions taking place during T cell activation and b) only a few studies investigate the role played by T cell tension. This project aims at understanding how forces contribute to T cell activation in a physiological context and at uncovering how cell tension orchestrates the cellular processes that underpin T cell activation. To do so, the projects will focus on three objectives: Objective 1: Characterise T cell transition from migration to activation, using a novel assay that we have developed in our research group.Objective 2: Determine how tension contributes to T cell activation, focusing on proteins at the interface between tension and the actin cytoskeleton and by using a cell stretching device.Objective 3: Understand the forces generated by dendritic cells, by measuring these forces using traction force microscopy in presence of T cell co-stimulatory receptors.

• DFG Programme: Research Grants