What Is the Right Mechanical Readout for Understanding the Mechanobiology of the Immune Response?

Abstract

Mechanobiology is a critical frontier in the biomedical sciences. Across many of its fields a new perspective is emerging to perceive the immune response as a single multi-scale super-organism continuously interacting and interpreting the biochemical and biomechanical micro-environment. Large numbers of immune cells communicate through a combination of chemical and mechanical signals to organise and orchestrate their behaviour and function against an immunological threat. However, disease often circumvents and even exploits mechanobiological features of this defence machinery, highlighting the need to better understand the intimate coupling between biology and mechanics. Mechanical force underpins the immune response at the multi-scale (Fritzsche, 2020). While almost all physical forces relevant to immune cell biology are practically restricted to the sub-cellular level such as electrostatics (e.g., receptor ligand binding) and thermodynamics (e.g., molecule diffusion), biomechanics takes on a special importance as mechanical force influences many functional features and behavior of immune cells over multiple scales in space and time (Dumont and Prakash, 2014; Egan et al., 2015). Mechanics contributes to the dynamics of single molecules, cells, tissues, and entire organisms (Blanchard and Adams, 2011; Chen and Zhu, 2013). The effects on the biology result from contributions of mechanics that are combination of those generated locally and those that influence from a distance. Importantly, both mechanical force and mechanical properties differ at distinct spatio-temporal frequencies such as constant and oscillatory forces, tension, or elasticity and viscosity (see Figure 1), respectively. For example, living cells can be elastic, viscous, or visco-elastic depending on the spatial and temporal measurement frequency (see Figure 1A). Adequate quantification promises thus a deeper understanding of the multi-scale spatio-temporal coupling of biology and mechanics and its control over the immune response (Fritzsche, 2020). Figure 1. (A) Schematic of the T cell (left) and Target cell (right) interplay. (B) Explanation of the mechanical metric tension with tensile stress σ in units of N/m² and tensile strain ε being dimenionless, and shear with shear stress τ in N/m², as well as the elasticity with Youngst modulus E, which equals the ratio of stress over strain. The stiffness of a material is given by EA/l. (C) Cells are elastic, viscous, or visco-elastic. Central to the immune defense against an invading threat is a well-orchestrated sequence of events carried out by specialized cells of the multi-scale super-organism of the immune system (Chaplin, 2010). The Success of the process relies on the quality of the spatiotemporal organization of the cellular responses in the tissue micro-environment of the host organism for instance against cancer or an invading pathogenic threat (Swartz and Lund, 2012). Cytotoxic immune cells circulate through tissue, track soluble cytokines and chemokines, respond to antigens, and kill diverse immuno-targets (Andersen et al., 2006; Grivennikov et al., 2010). Among many of these events, they involve a combination of biological and mechanical spheres of influence, as immune cells continuously interact and interpret the physical surroundings (Colin-York et al., 2016; Schwarz, 2017). This environment is also mechanically diverse over scales of space and time. It is comprised of different types of molecules, cells, and tissues (Needleman and Dogic, 2017). Mechanical aspects of the tissue environment are known to influence both the function and behavior of cells (Schwarz, 2017; Colin-York and Fritzsche, 2018). The complex multi-scale nature of mechanical force may have evolutionary been the reason for immune cells to develop the ability to adjust their own biomechanics to their physiological needs in response to the ever-changing physical world. Strikingly, when cells loose mechanosensation, the immune response is hampered to robustly and/or reliably achieve its protective function, which has been demonstrated for example during cell-cell interactions such as activation and cytotoxicity (Huse, 2017; Kumari et al., 2019), as well as during cellular interactions with the tumor micro-environment (Mohammadi and Sahai, 2018; Majedi et al., 2020). Consequently, this gives a special significance to mechanobiology of being important for the understanding of the functioning of the immune response as a whole in health and disease. One of the most illustrative and visually impressive examples for the impact of mechanobiology is the activation of T cells and antigen presenting cells (APCs) (Chen and Zhu, 2013; Harrison et al., 2019). Micron-scale ruffles protruding from the T cell initiate contact and binding between T cell receptors (TCRs) and the APC's peptide-loaded major hist-compatibility complexes (pMHCs) (Fritz-Laylin et al., 2017; Fritzsche et al., 2017). In the event of recognition and binding of pMHCs by a TCR, the T cell rearranges, assisted by its cytoskeleton, the totality of its metabolism, inner organelles, membrane, and its surface receptors and ligands (English and Voeltz, 2013; Maciver et al., 2013; Carlton et al., 2020). Strikingly, physical symmetry plays a major factor in these re-arrangements, possibly because of the need to balance and direct mechanical force between the T cell and the APC (Sims et al., 2007; Dustin, 2009; Arsenio et al., 2015). Calcium release in response to TCR-pMHC binding leads to the depolymerisation of microtubules, which in turn facilitates the rearrangement of organelles such as the nucleus and endoplasmic reticulum to the center of the T-cell body volume (Joseph et al., 2014; Ilan-Ber and Ilan, 2019). Cytoskeletal ruffles depolymerise and actin-rich lamellum and lamellipodium polymerise at the contact between both cells. The...