Three-Dimensional Gradients of Cytokine Signaling between T Cells

Abstract

Immune responses are regulated by diffusible mediators, the cytokines, which act at sub-nanomolar concentrations. The spatial range of cytokine communication is a crucial, yet poorly understood, functional property. Both containment of cytokine action in narrow junctions between immune cells (immunological synapses) and global signaling throughout entire lymph nodes have been proposed, but the conditions under which they might occur are not clear. Here we analyze spatially three-dimensional reaction-diffusion models for the dynamics of cytokine signaling at two successive scales: in immunological synapses and in dense multicellular environments. For realistic parameter values, we observe local spatial gradients, with the cytokine concentration around secreting cells decaying sharply across only a few cell diameters. Focusing on the well-characterized T-cell cytokine interleukin-2, we show how cytokine secretion and competitive uptake determine this signaling range. Uptake is shaped locally by the geometry of the immunological synapse. However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (≥20% of secretion). Hence paracrine signaling will generally extend beyond the synapse but can be limited to cellular microenvironments through uptake by target cells or strong competitors, such as regulatory T cells. By contrast, long-range cytokine signaling requires a high density of cytokine producers or weak consumption (e.g., by sparsely distributed target cells). Thus in a physiological setting, cytokine gradients between cells, and not bulk-phase concentrations, are crucial for cell-to-cell communication, emphasizing the need for spatially resolved data on cytokine signaling.

Sensing relative signal in the Tgf-β/Smad pathway

“…Our present work places the Tgf-β pathway among the increasing number of signaling pathways where fold-change response has now been identified or proposed (2,3,(7)(8)(9). Our finding reinforces an emerging theme across signaling pathways in animal cells, that signaling dynamics are sensed in a relative manner.…”

“…Detecting fold change in signal level allows a cell to assign meaning to signal relative to its own background, enabling faithful transduction despite cellular variability. In addition to the Wnt pathway, fold-change detection has been proposed in the Erk pathway (2) and, subsequently, in the NF-κB pathway (3), calcium signaling (8), and cytokine signaling (9). The evidence for foldchange detection in more and more systems suggests a conserved strategy across signaling pathways in animal cells.…”

Substrate-bound CCL21 and ICAM1 combined with soluble IL-6 collectively augment the expansion of antigen-specific murine CD4+ T cells

“…Clustered T cells secrete various regulatory factors with autocrine and paracrine activity, and the close proximity of cells within the cluster facilitates intercellular communication in a regulated microenvironment. 3,40,43,44 On the other hand, large T-cell clusters may limit or even downregulate T-cell proliferation by restricting the cells' access to essential signals or nutrients, or even by creating inhibitory environmental conditions. For example, clustering was shown to limit cytotoxic T-cell effector function and differentiation by limiting the T cells' exposure to antigen during activation, upregulating inhibitory receptors (CTLA-4) and downregulating the expression of effector molecules.…”

Deciphering the genomic toolkit underlying animal-bacteria interactions – insights through the demosponge Amphimedon queenslandica

“…Another form of intercellular communication, typically deployed in the context of the mammalian immune response, is paracrine signalling through the activity of cytokines (Lacy and Stow 2011;Thurley, et al 2015). Cytokines like TNF and TGF-β trigger behavioural changes or differentiation of nearby celltypes through paracrine signalling in mammals (Derynck and Akhurst 2007;Caldwell, et al 2014), and the upregulation of these cytokines in my experiments suggests they too could participate in coordinating the sponge cellular response to bacteria.…”