IL7 receptor signaling in T cells: A mathematical modeling perspective

Abstract

Interleukin‐7 (IL7) plays a nonredundant role in T cell survival and homeostasis, which is illustrated in the severe T cell lymphopenia of IL7‐deficient mice, or demonstrated in animals or humans that lack expression of either the IL7Rα or γ c chain, the two subunits that constitute the functional IL7 receptor. Remarkably, IL7 is not expressed by T cells themselves, but produced in limited amounts by radio‐resistant stromal cells. Thus, T cells need to constantly compete for IL7 to survive. How T cells maintain homeostasis and further maximize the size of the peripheral T cell pool in face of such competition are important questions that have fascinated both immunologists and mathematicians for a long time. Exceptionally, IL7 downregulates expression of its own receptor, so that IL7‐signaled T cells do not consume extracellular IL7, and thus, the remaining extracellular IL7 can be shared among unsignaled T cells. Such an altruistic behavior of the IL7Rα chain is quite unique among members of the γ c cytokine receptor family. However, the consequences of this altruistic signaling behavior at the molecular, single cell and population levels are less well understood and require further investigation. In this regard, mathematical modeling of how a limited resource can be shared, while maintaining the clonal diversity of the T cell pool, can help decipher the molecular or cellular mechanisms that regulate T cell homeostasis. Thus, the current review aims to provide a mathematical modeling perspective of IL7‐dependent T cell homeostasis at the molecular, cellular and population levels, in the context of recent advances in our understanding of the IL7 biology.This article is categorized under: Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods

Diffusion-limited cytokine signaling in T cell populations

“…Quite interestingly, strong positive feedback induced a decay and strong negative feedback induced an increase in measures of spatial cytokine inhomogeneity (Figure 3E and S4H-I), due to opposed effects on signal localization. This change in signal localization results in a similar change in cytokine signaling efficacy (Figure 3F), which is in line with the notion of the IL-7 receptor as an ‘altruistic’ signaling mediator 39 , as IL-7 uptake is stopped upon signal reception, so that cells further away from the cytokine-secreting cell are able to receive cytokine molecules.…”

“…Considering IL-7 as a cytokine promoting negative feedback on receptor expression, we observed an increase in signaling range that propagates with time, resembling a signaling wave that spreads through the cell population. That phenomenon is well in-line with the notion of IL-7 responder cells as ‘altruistic’ 39 , since they provide access to IL-7 to nearby cells by downregulating their receptors.…”

“…While IL-2 signaling in the local environment created by antigen-presenting cells facilitates fast and unambiguous decision-making on T cell activation, it has been argued that IL-7, a cytokine essential for T cell survival, should be distributed more widely within the system 39 . Our results on the spatio-temporal effects of negative feedback (cf.…”

Algebraic Study of Receptor-Ligand Systems: A Dose-Response Analysis

“…Two motivating examples: IL-7 cytokine receptor as a paradigm. We now consider the cytokine interleukin-7 (IL-7) and its receptor (IL-7R) [45,50,23,32,8,46] as a motivating receptor-ligand system. IL-7 is a cytokine involved in T cell development, survival, and homeostasis [36].…”

“…The binding of a ligand to its receptor induces an intracellular cascade of signaling events which regulate a cell's fate, such as migration, proliferation, death, or differentiation [39,60]. Receptor-ligand interactions are essential in cell-to-cell communication, as is the case for immune cell populations [17] and, thus, a large body of literature has been devoted to the experimental and theoretical study of cell signaling dynamics [64,49,23,50,32,31,46,41,20]. Exploiting the controlled environment of in vitro experiments, most cell signaling studies focus on the estimation of the affinity constant for a given receptor-ligand system, and the quantification of biochemical on and off rates for the binding and unbinding, respectively, of receptor and ligand molecules.…”