Functional consequences on T cell activation of mechanical input delivered by antigen-presenting cells

• Applicant: Dr. Jeremie Rossy
• Subject Area: Immunology ; Biophysics ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520916856

T lymphocytes, or T cells, play a central role in mounting an adaptive immune response because of their ability to produce a reaction tailored to the type and context of the inflammation, whether it be an infection or a developing tumour. This ability is related to the specific nature of the T cell activation process, which is achieved through a highly specialised interface with antigen-presenting cells, the immunological synapse. Antigen-presenting cells activate and instruct T cells through a dedicated ligand-receptor system at the synapse. In a recent project, we have uncovered that dendrtic cells, which are professional antigen-presenting cells, additionally deliver a mechanical signal to T cell through the immunological synapse. The key objectives of the proposed project are to understand how a mechanical input, such as the one generated by dendritic cells, can impact on the mechanisms and outcome of T cell activation. To do so, we will use a validated cell stretcher, which can generate a stress pattern similar to the forces produced by dendritic cells at the synapse. In a first objective, we will determine how external forces can regulate key processes and signalling pathways related to T cell activation, using the stretcher in combination with fluorescent reporters in live cells microscopy. In a second objective, we will change scale and adopt a multiomics approach based on single cell sequencing. We will simultaneously quantify epigenetic changes in chromatin organisation using ATACseq (Assay for Transposase-Accessible Chromatin using sequencing) and gene expression (RNAseq) in single T cells in response to extremally applied mechanical stress. Altogether, the data generated in the proposed research will provide us with a comprehensive understanding of how mechanical input delivered by dendritic cells regulate the initiation of the adaptive immune response. By revealing and deciphering a previously unexplored way of cell-cell communication in the immune system, these results will help building better immunotherapies approaches.

• DFG Programme: Research Grants
• International Connection: Australia
• Cooperation Partner: Dr. Elizabeth Hinde