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Three-Dimensional Gradients of Cytokine Signaling between T Cells.

Thurley K, Gerecht D, Friedmann E, Höfer T - PLoS Comput. Biol. (2015)

Bottom Line: However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (≥20% of secretion).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany; Institute for Theoretical Biology, Charité-Universitätsmedizin, Berlin, Germany; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.

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.

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Paracrine cytokine signals depend on cell density and receptor number.(A) Cytokine secretion and uptake is followed by receptor internalization, leading to a reduced cytokine concentration in the medium. (B) Schematic of the high cell-density scenario. A cytokine secreting cell is surrounded by a layer of responder cells that provide a diffusion barrier for the cytokine. Signaling can be autocrine (Jauto), i.e. cytokine molecules are bound by receptors of the cytokine secreting cell, or paracrine (Jpara), i.e. bound by receptors on responder cells. (C) Cytokine concentration profile in the model with homogeneous secretion and uptake. (D) Cytokine concentration 1 μm away from the cytokine secreting cell, in the limits of high and low cell-density. (E) Paracrine signal Jpara and autocrine signal Jauto (inset) as fraction of secreted cytokine molecules. (F) Autocrine and paracrine uptake in the high cell-density scenario. Dotted lines are approximations in the limit of fast diffusion (see S1 Text). Parameter values: R = 4000 mol./cell, and see Table 1.
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pcbi.1004206.g001: Paracrine cytokine signals depend on cell density and receptor number.(A) Cytokine secretion and uptake is followed by receptor internalization, leading to a reduced cytokine concentration in the medium. (B) Schematic of the high cell-density scenario. A cytokine secreting cell is surrounded by a layer of responder cells that provide a diffusion barrier for the cytokine. Signaling can be autocrine (Jauto), i.e. cytokine molecules are bound by receptors of the cytokine secreting cell, or paracrine (Jpara), i.e. bound by receptors on responder cells. (C) Cytokine concentration profile in the model with homogeneous secretion and uptake. (D) Cytokine concentration 1 μm away from the cytokine secreting cell, in the limits of high and low cell-density. (E) Paracrine signal Jpara and autocrine signal Jauto (inset) as fraction of secreted cytokine molecules. (F) Autocrine and paracrine uptake in the high cell-density scenario. Dotted lines are approximations in the limit of fast diffusion (see S1 Text). Parameter values: R = 4000 mol./cell, and see Table 1.

Mentions: The binding of cytokines to their high-affinity receptors is followed by receptor internalization and intracellular cytokine degradation, so that cytokine molecules are removed from the medium (Fig 1A). Thus, regulating the strength of cytokine signaling by cytokine receptor expression might also affect the extracellular cytokine concentration and hence, indirectly, signaling. To gain quantitative insight, we first studied a simple reaction-diffusion model, where a cytokine-secreting cell is surrounded by cells that can take up the cytokine. To allow for an analytical solution, we assume the surrounding cells to be placed on a spherical shell with the secreting cell in the center (Fig 1B, see Materials and Methods). For convenience, parameter values are summarized in Table 1. If the target cells are located far away (i.e., their density is low), the cytokine concentration experienced by the target cells is nearly independent of the level of receptor expression (Fig 1C) because the dilution of the cytokine occurs primarily by diffusion in the three-dimensional tissue. On the other and, if the density of target cells is so high that they immediately surround the cytokine secreting cell, the cytokine concentration is practically homogeneous in the small intervening space, as the timescale of diffusion over such a short distance is fast compared to the timescale of cytokine uptake (Fig 1D and S1 Text). As a consequence, the cytokine concentration experienced by proximal target cells is set by the balance of secretion rate by the cytokine-producing cell and uptake rate. The autocrine and paracrine uptake rates Jauto and Jpara depend on the level of cytokine receptor expression on the target cells (Fig 1E), and are practically independent of the cell-to-cell distance even at high cell density (Fig 1F; the low cell-density scenario is independent of the cell-to-cell distance by construction). Interestingly, cytokine concentration (Fig 1C) and uptake rates (Fig 1D) are sensitive to receptor expression on proximal targets cells in the physiologic range of 100 to several 1000 receptor molecules per cell [5]. Thus, this simple model indicates that with a high density of target cells, cytokine receptor expression controls the amount of paracrine cytokine signal.


Three-Dimensional Gradients of Cytokine Signaling between T Cells.

Thurley K, Gerecht D, Friedmann E, Höfer T - PLoS Comput. Biol. (2015)

Paracrine cytokine signals depend on cell density and receptor number.(A) Cytokine secretion and uptake is followed by receptor internalization, leading to a reduced cytokine concentration in the medium. (B) Schematic of the high cell-density scenario. A cytokine secreting cell is surrounded by a layer of responder cells that provide a diffusion barrier for the cytokine. Signaling can be autocrine (Jauto), i.e. cytokine molecules are bound by receptors of the cytokine secreting cell, or paracrine (Jpara), i.e. bound by receptors on responder cells. (C) Cytokine concentration profile in the model with homogeneous secretion and uptake. (D) Cytokine concentration 1 μm away from the cytokine secreting cell, in the limits of high and low cell-density. (E) Paracrine signal Jpara and autocrine signal Jauto (inset) as fraction of secreted cytokine molecules. (F) Autocrine and paracrine uptake in the high cell-density scenario. Dotted lines are approximations in the limit of fast diffusion (see S1 Text). Parameter values: R = 4000 mol./cell, and see Table 1.
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pcbi.1004206.g001: Paracrine cytokine signals depend on cell density and receptor number.(A) Cytokine secretion and uptake is followed by receptor internalization, leading to a reduced cytokine concentration in the medium. (B) Schematic of the high cell-density scenario. A cytokine secreting cell is surrounded by a layer of responder cells that provide a diffusion barrier for the cytokine. Signaling can be autocrine (Jauto), i.e. cytokine molecules are bound by receptors of the cytokine secreting cell, or paracrine (Jpara), i.e. bound by receptors on responder cells. (C) Cytokine concentration profile in the model with homogeneous secretion and uptake. (D) Cytokine concentration 1 μm away from the cytokine secreting cell, in the limits of high and low cell-density. (E) Paracrine signal Jpara and autocrine signal Jauto (inset) as fraction of secreted cytokine molecules. (F) Autocrine and paracrine uptake in the high cell-density scenario. Dotted lines are approximations in the limit of fast diffusion (see S1 Text). Parameter values: R = 4000 mol./cell, and see Table 1.
Mentions: The binding of cytokines to their high-affinity receptors is followed by receptor internalization and intracellular cytokine degradation, so that cytokine molecules are removed from the medium (Fig 1A). Thus, regulating the strength of cytokine signaling by cytokine receptor expression might also affect the extracellular cytokine concentration and hence, indirectly, signaling. To gain quantitative insight, we first studied a simple reaction-diffusion model, where a cytokine-secreting cell is surrounded by cells that can take up the cytokine. To allow for an analytical solution, we assume the surrounding cells to be placed on a spherical shell with the secreting cell in the center (Fig 1B, see Materials and Methods). For convenience, parameter values are summarized in Table 1. If the target cells are located far away (i.e., their density is low), the cytokine concentration experienced by the target cells is nearly independent of the level of receptor expression (Fig 1C) because the dilution of the cytokine occurs primarily by diffusion in the three-dimensional tissue. On the other and, if the density of target cells is so high that they immediately surround the cytokine secreting cell, the cytokine concentration is practically homogeneous in the small intervening space, as the timescale of diffusion over such a short distance is fast compared to the timescale of cytokine uptake (Fig 1D and S1 Text). As a consequence, the cytokine concentration experienced by proximal target cells is set by the balance of secretion rate by the cytokine-producing cell and uptake rate. The autocrine and paracrine uptake rates Jauto and Jpara depend on the level of cytokine receptor expression on the target cells (Fig 1E), and are practically independent of the cell-to-cell distance even at high cell density (Fig 1F; the low cell-density scenario is independent of the cell-to-cell distance by construction). Interestingly, cytokine concentration (Fig 1C) and uptake rates (Fig 1D) are sensitive to receptor expression on proximal targets cells in the physiologic range of 100 to several 1000 receptor molecules per cell [5]. Thus, this simple model indicates that with a high density of target cells, cytokine receptor expression controls the amount of paracrine cytokine signal.

Bottom Line: However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (≥20% of secretion).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany; Institute for Theoretical Biology, Charité-Universitätsmedizin, Berlin, Germany; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.

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.

Show MeSH