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A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-To- Cell Communication in the Immune System

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A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-To- Cell Communication in the Immune System Article A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to- Cell Communication in the Immune System Graphical Abstract Authors Alon Oyler-Yaniv, Jennifer Oyler-Yaniv, Benjamin M. Whitlock, ..., Morgan Huse, Gre´ goire Altan-Bonnet, Oleg Krichevsky Correspondence [email protected] (G.A.-B.), [email protected] (O.K.) In Brief Cytokine-mediated communication allows immune cells to achieve a context- appropriate response, but the distance over which this communication happens is unclear. Oyler-Yaniv et al. (2017) show that a simple diffusion-consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell-to-cell variability. Highlights d Cytokine penetration in tissues is governed by a diffusion- consumption mechanism d Spherical cytokine niches are generated around cytokine- producing cells d The characteristic niche size depends on the density of cytokine consumers d Cytokine niches are a source of variability in otherwise identical cells Oyler-Yaniv et al., 2017, Immunity 46, 609–620 April 18, 2017 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.immuni.2017.03.011 Immunity Article A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System Alon Oyler-Yaniv,1,2,3,4 Jennifer Oyler-Yaniv,2,3,4,5 Benjamin M. Whitlock,3,4,6 Zhiduo Liu,7 Ronald N. Germain,7 Morgan Huse,4 Gre´ goire Altan-Bonnet,2,3,4,9,* and Oleg Krichevsky1,3,4,8,* 1Physics Department, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel 2ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21701, USA 3Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 4Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 5Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA 6Biochemistry and Molecular Biology Graduate Program, Weill-Cornell Medical College, New York 10065, USA 7Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA 8Ilse Kats Center for Nanoscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel 9Lead Contact *Correspondence: [email protected] (G.A.-B.), [email protected] (O.K.) http://dx.doi.org/10.1016/j.immuni.2017.03.011 SUMMARY and doses of stimuli. Diversity is often achieved through spatial gradients in the concentration of diffusible ligands. A cell’s Immune cells communicate by exchanging cytokines position within the gradient is translated to downstream fate to achieve a context-appropriate response, but the decisions. distances over which such communication happens Gradients of soluble molecules could arise by pure diffusion are not known. Here, we used theoretical consid- from a source, by diffusion coupled to biochemical degradation, erations and experimental models of immune re- or by diffusion coupled to consumption of the molecule. In the sponses in vitro and in vivo to quantify the spatial latter two cases, gradients will have a characteristic length- scale: the typical distance over which cytokine interactions extent of cytokine communications in dense tissues. persist, which is determined by a balance between diffusion We established that competition between cytokine and degradation or consumption. Specifically, when consump- diffusion and consumption generated spatial niches tion is the predominant mechanism of removing molecules of high cytokine concentrations with sharp bound- from the system, we expect this length scale to depend on the aries. The size of these self-assembled niches abundance and efficiency of consumers. Alternatively, if mole- scaled with the density of cytokine-consuming cells, cules are removed primarily via molecular degradation, this a parameter that gets tuned during immune re- length scale will be independent of cellular composition. Indeed, sponses. In vivo, we measured interactions on length it has been shown that a model of diffusion coupled to consump- scales of 80–120 mm, which resulted in a high degree tion is the mode of morphogen spreading during development of cell-to-cell variance in cytokine exposure. Such (Wartlick et al., 2009). heterogeneous distributions of cytokines were a Immune cells rely on a network of diffusible cytokine mediators that enable cell-to-cell communication. Cytokines broadcast source of non-genetic cell-to-cell variability that is the magnitude and nature of pathogenic insults, scale the immune often overlooked in single-cell studies. Our findings response, and determine lymphocyte fate through transcription thus provide a basis for understanding variability in factor activation (Paul and Seder, 1994). A vast array of different the patterning of immune responses by diffusible cytokines exist that bind strongly to their cognate receptors, often factors. with characteristic binding affinities in the nano- or pico-molar range. An effective immune system must be flexible enough to combat various types and doses of pathogen while minimizing INTRODUCTION collateral tissue damage caused by inflammation. A key difference between the case of the developing embryo The evolution of multi-cellular organisms is made possible by a and that of the immune system is that the latter requires plas- division of labor across different cell types. Differentiation of pre- ticity. Development necessitates accuracy and precision, so cursors into diverse and specialized cell types is often mediated morphogen gradients must contribute to robustness in the spatial by diffusible extracellular stimuli, such as morphogens, growth pattern of gene expression across individuals (Houchmandzadeh factors, or cytokines. To generate diverse fates, cells must et al., 2002). In contrast, an effective immune system must be occupy diverse environments characterized by variable types flexible enough to combat various types and doses of pathogen. Immunity 46, 609–620, April 18, 2017 Published by Elsevier Inc. 609 This implies that the immune system must have a tunable length (Snijder and Pelkmans, 2011). Next, we presented measurements scale of cell-to-cell communication that determines the extent of of the spatial extent of cytokine-mediated interaction in vivo. We its action in response to a given threat. tested our theory in vivo by increasing the density of cytokine- It is critical to consider how the length scales of communica- consuming cells and measuring the decrease in the size of the tion compare to the overall size of an organ. Communications niches during an immune response. Finally, we examined an inde- that happen over length scales that are comparable to or larger pendent dataset involving resting lymph nodes in which the source than the organ result in homogeneous cytokine fields (Perona- and spread of IL-2 could be determined. The experimental data Wright et al., 2010). In these conditions, the system is approxi- were in agreement with the theoretical predictions on the shape mately well-mixed, with cells responding uniformly. In contrast, of the cytokine field and its spatial propagation extent around a communications on length scales much smaller than the size secreting cell. Overall, we observed that the density of cytokine re- of the organ will result in heterogeneity in cytokine exposure ceptors dynamically regulates how far a cytokine spreads from its and localized domains of high cytokine concentrations (Maldo- site of production during an immune reaction. nado et al., 2004; Pangault et al., 2010; Sabatos et al., 2008; Thurley et al., 2015), i.e., niches. This heterogeneity in cytokine RESULTS exposure translates to variability in cellular response (e.g., tran- scription factor activation), which results in divergent paths of The Size of the Regulatory T Cell Pool Is Dynamic and differentiation and/or proliferation for individual cells (Snijder Dependent on the System’s State of Activation and Pelkmans, 2011). It has long been appreciated that the size of the Treg cell pool Quantifying how far cytokines spread from their source, and and the expression level of IL-2Ra can be tuned by endoge- the gradients they form, is a prerequisite for explaining how these nously-produced and exogenously-administered IL-2 (Amado cytokines generate the immense phenotypic and functional het- et al., 2013; Boyman et al., 2006a; Spangler et al., 2015; Webster erogeneity observed in immune cell populations (Busse et al., et al., 2009). For example, administration of particular IL-2-aIL-2 2010; Feinerman et al., 2010; Ho¨ fer et al., 2012; Muller€ et al., complexes augments the Treg cell pool, increasing the number 2012; Thurley et al., 2015). In this study, we used theoretical con- of cells and their IL-2Ra expression level (Boyman et al., siderations and direct experimental testing in vitro and in vivo to 2006a; Spangler et al., 2015). Given that one key function of quantify cytokine tissue penetration. We show that the spatial Treg cells is to scavenge IL-2 (Fontenot et al., 2005; Ho¨ fer extent of cytokine signaling is a dynamic parameter, which is et al., 2012; Pandiyan et al., 2007), this system presents an ideal tuned by the state and extent of lymphocyte activation. model to learn how the length scale of cytokine signaling During an immune response, activated CD4+ effector T (Teff) changes based on the density of cytokine-consuming cells. cells produce a variety of cytokines. In particular, interleukin-2 To determine the plasticity in the size of the Treg cell compart- (IL-2) is produced transiently for several hours following activation ment during an actual immune response, TCR transgenic CD4+ through the T cell receptor (Figure S1, Helmstetter et al., 2015; T cells specific for moth cytochrome c peptide (5C.C7) were Huang et al., 2013; Sojka et al., 2004) and serves a critical role adoptively transferred (AdTr) into B10.A wild-type recipient as a differentiation and proliferation factor (Heltemes-Harris mice.
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