Biomechanical mechanisms of immune cell activity

• Applicant: Professorin Dr. Ana-Suncana Smith
• Subject Area: Biophysics ; Biomaterials ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465217725

Inhibitory receptors of T cells and natural killer (NK) cells sustain self-tolerance of the immune system and prevent collateral damage during a physiological immune response. It has long been hypothesized that the biological function of activating and inhibitory receptors, besides on chemical recognition, depends on their biomechanical characteristics such as length, flexibility, bond-strength and spatial arrangement. Yet, quantitative measurements of cell activation as a function of the mentioned biomechanical parameters are challenging and largely missing. Similarly, mathematical models accounting for the biomechanics of the adherent cells are scarce and insufficient to predict or rationalize the potential dependencies. Therefore, it remains difficult to clearly relate the spatial organization of inhibitory and activating receptors, the biomechanical properties of their bonds, and the properties of the surrounding membrane with the cell performance. Here we propose a synergistic experimental and modeling approach that aims at clearly identifying the role of ligand-receptor biomechanics and the effect of spatial organization and patterning of bonds in the membrane on T and NK cell activation. To reach our aim we devise a highly interdisciplinary approach that combines the unique expertise of the PIs and the project team in nanotechnology, NK/ T cell biology, imaging, and the physics of the cell membrane. The key will be to circumvent the technical difficulties associated with simultaneously manipulating the formation of inhibitory and activating ligand-receptor bonds, by changing their properties and patterns. To achieve this, we will build on our preliminary work where we nanofabricated arrays of variably spaced nanodots of two metals each selectively functionalized with activating and inhibitory ligands. We used these arrays as surrogate platforms for the stimulation of NK cells and found that the activation signaling and immune response varied with the spacing. This result was rationalized by theoretical modeling which showed that there is an optimal distance between the two pairs at which binding is promoted. Expanding on this effort, we will pursue three specific goals: (i) We will explore the effect of the molecular scale proximity between activating and inhibitory receptors on their signal integration in T and NK cells in the environment of the fluctuating active cell membrane. (ii) We will analyze the cumulative effect of the ligand spatial arrangement, size, and flexibility on their signal integration. (iii) Finally, we will determine the role of the nano-clustering of activating and inhibitory receptors on their signal integration. With this comprehensive approach, we will shed the light on the mechanism of the receptors signaling and regulation of our immune system, whose propound understanding is both fundamentally important and critical for the rational design of future immunotherapy.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Mark Schvatzman