Contribution of whole-cell optimization via cell body rolling to polarization of T cells

Abstract

Directed secretion of cytotoxins or cytokines by T cells during immune response depends on migration of the centrosome in the T cell to the interface with the target cell. The mechanism of the centrosome translocation has been elusive. The presented computational analysis demonstrates that the centrosome should be positioned at the interface if the T cell attempts simultaneously a) to minimize its surface area, b) to maximize the interface area, c) to maintain the cell volume, and d) to straighten the microtubules. Live three-dimensional microscopy and measurements show that the optimal position of the centrosome is achieved in large part (by about 40%) via rolling of the entire T cell body on the target surface, which movement appears to entrain the centrosome. The theoretical and experimental results draw attention to the previously unrecognized role of the whole-cell structure and whole-cell movements in the T cell polarization.

An Experimental and Computational Study of Effects of Microtubule Stabilization on T-Cell Polarity

“…The approximation of the microtubule cytoskeleton with the smaller number of more rigid chains of segments can be valid if the chains are sufficiently numerous to represent adequately the shapes of all microtubules in the cell (it is assumed that microtubules are not bundled). A numerical test shows that N sim  = 24, which value we employed previously [13] without rigorous testing, is sufficient, because the results of the energy minimization cease to depend on N sim beyond this number (Fig. 1).…”

“…Π = 3.4 fJ µm −3 is the oncotic pressure characteristic of mammalian tissues [18], and V eq  = 2.1 pL is the goal cell volume consistent with the characteristic size of the cells in our experiments [13]. V ( X ) is the value of the variable cell volume corresponding in the above geometrical sense to the microtubule conformation specified by X .…”

Systems biomechanics of centrosome positioning

“…The calculations reveal a rugged, pitted energy landscape, in which the global minimum corresponding to the biologically functional centrosome orientation is surrounded by multiple local minima, where the system may "get stuck" on the way down the energy gradient, without ever reaching the global minimum. 27 These computational findings may explain why redundancy appears to be sought by the cell, P 1 or T. The overall reliability of centrosome positioning, in the face of the biophysical constraints on each mechanism, should be increased when both are deployed in parallel. Considering the complexity that seems to permeate the centrosome positioning mechanics, however, it remains to be examined if this conjecture can stand the test of rigorous analysis.…”

“…1C) has no frame of reference in which its polarity must develop. The eccentric positioning of the centrosome in this case 9 corresponds simply to the energy minimum [27][28][29] of the microtubules, which are anchored at the centrosome and bend against the cell boundary. Calculations show that the elastic energy of bending is not minimized when all microtubules are bent equally.…”

“…It was established by means of computational analysis that positioning of the centrosome next to a flattened patch on the otherwise convex cell surface minimizes energy. 27,28 The energy in these calculations was taking into account a variety of contributing factors. Among them, the energy terms associated with bending of microtubules and with osmotic maintenance of the cell volume were found particularly important.…”