Stochasticity and spatial heterogeneity in T‐cell activation

Abstract

Stochastic and spatial aspects are becoming increasingly recognized as an important factor in T-cell activation. Activation occurs in an intrinsically noisy environment, requiring only a handful of agonist peptide-major histocompatibility complex molecules, thus making consideration of signal to noise of prime importance in understanding sensitivity and specificity. Furthermore, it is widely established that surface-bound ligands are more effective at activation than soluble forms, while surface patternation has highlighted the role of spatial relocation in activation. Here we consider the results of a number of models of T-cell activation, from a realistic model of kinetic segregation-induced T-cell receptor (TCR) triggering through to simple queuing theory models. These studies highlight the constraints on cell activation by a surface receptor that recruits kinases. Our analysis shows that TCR triggering based on trapping of bound TCRs in regions of close proximity that exclude large ectodomain-containing molecules, such as the phosphatases CD45 and CD148, can effectively reproduce known signaling characteristics and is a viable 'signal transduction' mechanism distinct from oligomerization and conformation-based mechanisms. A queuing theory analysis shows the interrelation between sensitivity and specificity, emphasizing that these are properties of individual cell functions and need not be, nor are likely to be, uniform across different functions. In fact, threshold-based mechanisms of detection are shown to be poor at ligand discrimination because, although they can be highly specific, that specificity is limited to a small range of peptide densities. Time integration mechanisms however are able to control noise effectively, while kinetic proofreading mechanisms endow them with good specificity properties. Thus, threshold mechanisms are likely to be important for rapidly detecting minimal signaling requirements, thus achieving efficient scanning of antigen-presenting cells. However, for good specificity, time integration on a scale of hours is required.

Lck and the nature of the T cell receptor trigger

“…The key requirement is a significant (order of magnitude) change in the net phosphorylation rate, which can be generated readily by decreasing the phosphatase activity within the close-contact zone [24].…”

A Division-Dependent Compartmental Model for Computing Cell Numbers in CFSE-based Lymphocyte Proliferation Assays

“…Recent work has indicated that the mechanisms responsible for cell proliferation and death may be mutually dependent upon a common molecular pathway [33,67]. As more data becomes available, we hope to examine how the estimated parameters change under various experimental conditions, with an eye toward additional constitutive relationships linking molecular and/or subcellular functions to population dynamics [25]. In this context, it seems necessary to consider the extent to which these functions and/or pathways are inherited.…”

Protein mediated membrane adhesion

“…Direct comparison between the reduced mathematical model given by (5), (9), and (10) and full model (1)-(4) for the membrane shape at different points in time are shown in Figure 5 demonstrate that the reduced model gives an accurate representation of the spatiotemporal features in this limit.…”

“…h(x, t × ϵ 2 = 15) is used as input to (5). (b) The results of full models (1)-(4) are shown using solid lines and those using reduced models (5), (9), and (10) are shown using dashed lines at two different points in time t × ϵ 2 = 7, 28.…”