Mechanisms of cell division as regulators of acute immune response

Abstract

The acute adaptive immune response is complex, proceeding through phases of activation of quiescent lymphocytes, rapid expansion by cell division and cell differentiation, cessation of division and eventual death of greater than 95 % of the newly generated population. Control of the response is not central but appears to operate as a distributed process where global patterns reliably emerge as a result of collective behaviour of a large number of autonomous cells. In this review, we highlight evidence that competing intracellular timed processes underlie the distribution of individual fates and control cell proliferation, cessation and loss. These principles can be captured in a mathematical model to illustrate consistency with previously published experimentally observed data.

Keywords: B lymphocytes; Cell division; Immune regulation; Mathematical modelling.

Fig. 1

A triggered clonal expansion as a result of antigen stimulation. Resting cells have different receptor affinities. Clones with sufficiently high affinity get stimulated and proliferate. The level of affinity modulates the extent of proliferation

Fig. 2

The operation of the Cyton model can be illustrated with two independent timers (hourglasses). Each timer is reset at cell birth with a different time. Whichever timer runs out first determines the fate of the cell, while the other fate remains unobserved. The division machinery is subject to division limit for a given clone. If the limit is reached (e.g., 3 divisions) then the division timer is not set, and death is the only fate

Fig. 3

State diagram for B cells under certain conditions (see text). Arrows indicate potential state transitions rather than necessary transitions. The diagram illustrates that death can occur at any point, and division can occur for activated cells. Both death and division censor all other events, whereas differentiation into a plasmablast censors isotype switching

Fig. 4

Different activation patterns of B cells. Cell division machinery is a hypothetical system associated with the speed of division, whereas division limit applies to the number of times a cell (clone) can divide. There is experimental evidence that the two machineries operate independently: CpG and LPS activation affects only division limit, whereas αCD40 activation affects both

Fig. 5

Differentiation rate can be controlled through division mechanism. In this artificial example, a distribution for times to differentiate is fixed (lognormal, mean 13.7 h, SD 2.8 h), but distributions for times to divide vary (both lognormal; left mean 11.2 h, SD 2.3 h; right mean 9.2 h, SD 1.9 h). The bottom panels show corresponding bivariate distributions (contour plots, darker lines correspond to lower probabilities). Assuming no death or any other fates, cells with time to differentiate smaller than time to divide (below the blue line on the bivariate plots) will differentiate. In the first case (left), differentiated rate is about 24 %, whereas in the second case (right), the rate is only 8 %