Modeling T cell plasma membrane phase separation
Recent studies including those from the CIML host team suggest that upon T Cell Receptor triggering (TCR) by antigenic ligands, T cell plasma membrane undergoes a rapid change that allows the liquid-liquid phase separation segregating signaling molecules essential for the initiation of T cell activation. This event seems to be associated with significant changes in the membrane topography. Our hypothesis is that a modification of membrane curvature or a local change in membrane tension induced by TCR-ligand interactions could underline the phenomenon of phase separation observed in the T cell membrane.
In order to better understand the physical parameters that control this phase transition process, the PhD work will mainly concern the development of a mathematical and numerical modeling approach, using M2P2’s modelling expertise in the mechanics of biomimetic soft objects like vesicles. The modelling base developed at M2P2 includes: in plane surface elasticity and viscosity, curvature elasticities, mechanical interactions with cytoskeleton, surrounding fluids and substrates. Now, to address the question of signaling molecule diffusion in the fluid membrane, modelling this phenomenon must be considered.
M2P2 has developed a boundary element approach implemented in object-oriented language on CPU-GPU architecture with which the evolution of the membrane’s mechanical properties in interaction with his environment can be computed. Starting from this base and to address not only the diffusion of surface species but also phase separation, the Cahn-Hilliard’s theory of statistical physics will be investigated. Finding out the right form and parameters needs to couple to experiments and eventually to coarse graining simulations. CIML will provide live-imaging data describing membrane liquid phase behavior and molecular dynamics in live T cells interacting with TCR ligands or with adhesion molecules that don’t drive liquid phase separation. Also, a detailed description of the T cell topography, of the local membrane tension and of the cytoskeleton will be provided using advanced imaging techniques. Finally, according to modeling data, CIML will use strategies to modify membrane composition, tension or curvature to test the different hypotheses.
PhD student’s expected profile
Useful skills concern a broad spectrum of engineering sciences, namely mathematics (approximations of partial differential equations, differential geometry), physics (physics of fluids and soft-matter), mechanics (Stokes flows, elasticity), and computational sciences (object-oriented programming and high-performance computing). This educational background must be completed by a real interest in life sciences (cell biology, immunology) with a deep motivation and capacity to learn more to understand the biological issues. This PhD project is fundamentally interdisciplinary and will need to interact with researchers of both communities.