Biphasic mechanosensitivity of T cell receptor-mediated spreading of lymphocytes

Abstract

Mechanosensing by T cells through the T cell receptor (TCR) isat the heart of immune recognition. While the mechanobiology of the TCR at the molecular level is increasingly well documented, its link to cell-scale response is poorly understood. Here we explore T cell spreading response as a function of substrate rigidity and show that remarkably, depending on the surface receptors stimulated, the cellular response may be either biphasic or monotonous. When adhering solely via the TCR complex, T cells respond to environmental stiffness in an unusual fashion, attaining maximal spreading on an optimal substrate stiffness comparable to that of professional antigen-presenting cells. However, in the presence of additional ligands for the integrin LFA-1, this biphasic response is abrogated and the cell spreading increases monotonously with stiffness up to a saturation value. This ligand-specific mechanosensing is effected through an actin-polymerization-dependent mechanism. We construct a mesoscale semianalytical model based on force-dependent bond rupture and show that cell-scale biphasic or monotonous behavior emerges from molecular parameters. As the substrate stiffness is increased, there is a competition between increasing effective stiffness of the bonds, which leads to increased cell spreading and increasing bond breakage, which leads to decreased spreading. We hypothesize that the link between actin and the receptors (TCR or LFA-1), rather than the ligand/receptor linkage, is the site of this mechanosensing.mechanosensing | TCR | cell adhesion | T cell | cell spreading M echanosensitivity has emerged as a hallmark of many bio-

T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces

“…Contemporary approaches in biomaterials design have provided enhanced control over this branch of immunity, leading to new tools for medicine including vaccination and cellular immunotherapy. Intriguingly, tuning the mechanical rigidity of a substrate used to activate T cells can modulate their subsequent functions including cytokine secretion, proliferation, and population expansion (1)(2)(3)(4)(5). These studies have been carried out predominantly in the context of bulk materials that present to cells planar interfaces that are geometrically and mechanically simplistic.…”

Mechanical Regulation of the Cytotoxic Activity of Natural Killer Cells

“…However, it could be of interest to compare the observed behavior of NK cells to that of other lymphocytes stimulated in analogous conditions. As mentioned above, the effect of surface stiffness on immune activation was previously reported for T cells and B cells, but those reports used relatively short ranges of surface stiffnesses, and showed different stiffness versus activation trends that appeared to depend on the studied stiffness range (14)(15)(16)(17)(18)37) (Table 1). As mentioned, the combination of those studies for T cells suggested the possibility of a bell-shape correlation (6).…”

Membrane Organization and Physical Regulation of Lymphocyte Antigen Receptors: A Biophysicist’s Perspective

“…The comparative use of substrates exhibiting immobilised or mobile anti-CD3 in combination with cytoskeletal drugs evidenced the instrumental role of actin-receptor friction in T cell spreading (Dillard 2014). The same driving force produced by the actin retrograde flow was also proposed, in combination with ligand-receptor force dependent unbinding, to explain the optimal substrate stiffness observed for TCR-mediated spreading (Wahl 2019) (Figure 3C). The interaction of actin and TCR was also proposed to be responsible for TCR triggering by inducing conformational change upon ligand binding (Feng 2017).…”

“…The effect of ligand mobility was explored by comparing ligands on fluid lipid bilayers and the same ligands immobilised on glass, maintaining also a precise control and reduction of non-specific interactions (Dillard 2014). The effect underlying substrate stiffness was studied in a wide range using different types of elastomers (Wahl 2019). Patterning and substrate stiffness can also be controlled at the same time (Alameddine 2017).…”

“…In this context, Monte-Carlo simulations may help decipher quantitatively the respective roles of lateral crowding, binding protein affinity, and thermally-driven membrane height fluctuations in membrane proteins segregation (Schmid 2016), where cytoskeleton and activity are missing. More recently, a clutch model integrating cytoskeleton generated forces in bond kinetics was proposed to explain the non-monotonous spreading response of T-cells on substrates of increasing rigidity (Wahl 2019). At the cellular scale, phagocytosis of antibody opsonised particles was modelled with finite elements simulations, emphasising the role of cytoskeleton-receptor bonds in driving the phagocytic cup progression (Herant 2006).…”