Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments

Abstract

Cytokines are pleiotropic and readily diffusible messenger molecules, raising the question of how their action can be confined to specific target cells. The T cell cytokine interleukin-2 (IL-2) is essential for the homeostasis of regulatory T (Treg) cells that suppress (auto) immunity and stimulates immune responses mediated by conventional T cells. We combined mathematical modeling and experiments to dissect the dynamics of the IL-2 signaling network that links the prototypical IL-2 producers, conventional T helper (Th) cells, and Treg cells. We show how the IL-2-induced upregulation of highaffinity IL-2 receptors (IL-2R) establishes a positive feedback loop of IL-2 signaling. This feedback mediates a digital switch for the proliferation of Th cells and functions as an analog amplifier for the IL-2 uptake capacity of Treg cells. Unlike other positive feedbacks in cell signaling that augment signal propagation, the IL-2/IL-2R loop enhances the capture of the signal molecule and its degradation. Thus Treg and Th cells can compete for IL-2 and restrict its range of action through efficient cellular uptake. Depending on activation status and spatial localization of the cells, IL-2 may be consumed exclusively by Treg or Th cells, or be shared between them. In particular, a Treg cell can deprive a stimulated Th cell of its IL-2, but only when the cells are located in close proximity, within a few tens of micrometers. The present findings explain how IL-2 can play two disctinct roles in immune regulation and point to a hitherto largely unexplored spatiotemporal complexity of cytokine signaling.bi-stability | cell-to-cell communication | cytokine networks | mathematical modeling | reaction-diffusion systems

Polyfunctional responses by human T cells result from sequential release of cytokines

“…For example, the activation of individual T cells does not occur homogeneously upon stimulation-even isogenic ones-but rather activate in a digital (on/off) manner, resulting from variations in transcriptional activity or gene accessibility (25,26), the numbers and dynamic expression of signaling receptors (e.g., CD8, IL-2R), and regulators of both positive and negative feedback loops (e.g., ERK, SHP-1, and RAS) (23,30,38,39). Expression of IL-2 and IFN-γ in human CD4 + T cells has also been shown to depend on the categorical translocation of the transcription factor NFATc2 (24).…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…IL-2 receptor activation leads to reduced expression of IL-2, restricting autocrine stimulation, while levels of IL-2Ra remain high for continued paracrine surveillance (Smith and Popmihajlov 2008;Crispin and Tsokos 2009). Depending on co-receptor stimuli, activated T cells proliferate and undergo commitment into CD4þ (helper, Th) or CD8þ (cytotoxic T lymphocyte, Tc) (Williams and Bevan 2007;Busse et al 2010). The level of IL-2 signaling has also been shown to affect the development of non-terminally differentiated (quiescent) CD4þ and CD8þ memory cells, which are necessary for effective immune recall upon reinfection.…”

Asthma phenotyping, therapy, and prevention: what can we learn from systems biology?

“…The modeling of biochemical pathways involved in the regulation of the inflammatory response has been addressed in many papers during the past decade (74)(75)(76)(77)(78). Further, in the past few years several studies have adopted this approach to address some aspects of the molecular basis of asthma.…”

“…Also, using elegant single-cell measurements and modeling, Podtschaske et al showed that graded T-cell receptor signaling results in graded activation of the transcription factor nuclear factor κB, but a digital activation of transcription factor NFATc2 results in a switch that regulates the number of T lymphocytes actively participating in an immune response (82). In addition, cytokines such as IL-2, which have different effects on different populations of T lymphocytes, have also been studied by combined experimentation and modeling approaches specifically addressing the spatiotemporal complexity (75).…”