Deterministic Mechanical Model of T-Killer Cell Polarization Reproduces the Wandering of Aim between Simultaneously Engaged Targets

Abstract

T-killer cells of the immune system eliminate virus-infected and tumorous cells through direct cell–cell interactions. Reorientation of the killing apparatus inside the T cell to the T-cell interface with the target cell ensures specificity of the immune response. The killing apparatus can also oscillate next to the cell–cell interface. When two target cells are engaged by the T cell simultaneously, the killing apparatus can oscillate between the two interface areas. This oscillation is one of the most striking examples of cell movements that give the microscopist an unmechanistic impression of the cell's fidgety indecision. We have constructed a three-dimensional, numerical biomechanical model of the molecular-motor-driven microtubule cytoskeleton that positions the killing apparatus. The model demonstrates that the cortical pulling mechanism is indeed capable of orienting the killing apparatus into the functional position under a range of conditions. The model also predicts experimentally testable limitations of this commonly hypothesized mechanism of T-cell polarization. After the reorientation, the numerical solution exhibits complex, multidirectional, multiperiodic, and sustained oscillations in the absence of any external guidance or stochasticity. These computational results demonstrate that the strikingly animate wandering of aim in T-killer cells has a purely mechanical and deterministic explanation.

Centrosome positioning in vertebrate development

“…The centrosome moves to the immunological synapse by cortical pulling (Kim and Maly, 2009) and directs the delivery of lytic granules (Stinchcombe et al, 2006;Tsun et al, 2011) (Fig. 2D).…”

Systems biomechanics of centrosome positioning

“…For certain initial conditions (which in reality are unique for each cell), the "jamming" may become spontaneously resolved through a catastrophic stability loss of the static equilibrium in the "jammed" cell. 22 on asymmetrically toward a certain, as yet undiscovered, cortical site? Such a site, while being arbitrarily oriented in the laboratory frame of reference, could nonetheless provide a directional bias for the thermodynamic tendency of the cytoskeleton toward arbitrary eccentricity.…”

“…14 Kim and Maly 22 simulated the bending of the microtubules and the pulling force exerted on them by dynein that accumulates on the inner surface of the interface. 23,24 Similarly to the numerical models of the Caenorhabditis elegans zygote, they found that the equilibrium does not persist, and oscillations develop spontaneously.…”

“…22 Thus, the pulling on the leading side always wins, no matter which direction the centrosome is moving tountil the movement is ended by bending of the leading microtubules against the cell boundary. The microtubules that trailed then have time to relax elastically and come in contact with the pulling surface again to initiate the movement to the opposite side.…”

“…It was found by means of computational analysis that the dynein pulling in T cells can indeed "reel in" the centrosome to the cell-cell interface, even considering the significant biophysical constraints such as the molecular motor force, microtubule rigidity, and viscous resistance of the cytoplasm. 22 At the same time, the cited work demonstrated that the pulling mechanism of positioning is error-prone, and in fact unlikely to reorient the microtubule cytoskeleton by more than 90 degrees. One of the reasons for this stands out particularly clearly in the complexity of the cytoskeleton movements that are induced by the localized cortical pulling in the mechanical model.…”