title: A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System.
abstract: Immune cells communicate by exchanging cytokines to achieve a context-appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self-assembled niches scaled with the density of cytokine-consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80-120 μm, which resulted in a high degree of cell-to-cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non-genetic cell-to-cell variability that is often overlooked in single-cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors.
authors.affiliation: Physics Department, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel; ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21701, USA; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Oyler-Yaniv
authors.affiliation: ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21701, USA; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oyler-Yaniv
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Biochemistry and Molecular Biology Graduate Program, Weill-Cornell Medical College, New York 10065, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Whitlock
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhiduo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Huse
authors.affiliation: ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21701, USA; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.affiliation: Physics Department, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ilse Kats Center for Nanoscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: okrichev@bgu.ac.il.
authors.forename: Oleg
authors.initials: O
authors.lastname: Krichevsky
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004058:Diffusion; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor
keywords: Cell-to-cell communications; Cell-to-cell variability; Cytokine niches; Cytokines; Diffusion/Consumption; Interleukin-2; Quantitative Immunology; STAT5; Theoretical Modeling