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Cytokine-mediated communication: a quantitative appraisal of immune complexity

Nature Reviews Immunology volume 19, pages 205–217 (2019)Cite this article

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Abstract

Intercellular communication mediated by cytokines is the main mechanism by which cells of the immune system talk to each other. Many aspects of cytokine signalling in the immune system have been explored in great detail at the structural, biophysical, biochemical and cellular levels. However, a systematic understanding of the quantitative rules that govern cytokine-mediated cell-to-cell communication is still lacking. Here, we discuss recent efforts in the field of systems immunology to bring about a quantitative understanding of cytokine-mediated communication between leukocytes and to provide novel insights into the orchestration of immune responses and inflammation.

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Fig. 1: Three modes of cytokine-mediated cell-to-cell communication.
Fig. 2: The rate of cytokine consumption affects the signalling mode during an immune response.
Fig. 3: Variable confinement of cytokine-mediated communication within the T cell immunological synapse.
Fig. 4: Homeostasis by cytokine competition.

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Acknowledgements

Because of a need for conciseness and owing to space constraints, the authors could not systematically cite all studies of relevance to this Review, and they apologize to the authors of those studies that were omitted. The authors thank A. Belmonte and A. Zilman for discussions about modelling in the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway. This work was supported by the Intramural Research Program of the National Cancer Institute (Bethesda, MD, USA).

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Nature Reviews Immunology thanks R. Medzhitov and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Immunodynamics Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Grégoire Altan-Bonnet & Ratnadeep Mukherjee

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  1. Grégoire Altan-Bonnet
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The authors contributed equally to all aspects of the article.

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Correspondence to Grégoire Altan-Bonnet.

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Glossary

Autocrine

A form of cell-to-cell communication in which a cell secretes a cytokine (or any other soluble molecule) that binds to receptors on its own surface and elicits a signalling response.

Paracrine

A form of cell-to-cell communication in which a cell secretes a cytokine that binds to receptors on the surface of neighbouring cells and triggers a signalling response in these neighbouring cells.

Endocrine

A form of cell-to-cell communication in which a cell secretes a cytokine that reaches the blood circulation (hence triggering a more global response). It can be considered as an extended version of paracrine communication, and it applies to hormones as well as cytokines.

Effective concentration for half-maximum response

(EC50). The concentration of a cytokine that yields a half-maximum response.

Diffusion

The spontaneous motion of molecules down their concentration gradient (a passive mode of transport that is driven by thermal fluctuations).

Advection

The active transport of molecules driven by the flow of a fluid (blood or lymphatic fluid).

Linear function

In regimes of low cytokine concentration, the consumption rate for a given cytokine can be approximated as being proportional to the concentration of cytokine (linear dependency). When the cytokine receptors on the surface of cells are saturated with cytokines, the consumption rate reaches a plateau, becomes independent of the cytokine concentration in the extracellular milieu and introduces nonlinearities to the equations that describe its behaviour.

International units per millilitre

An ad hoc unit that is the cytokine concentration for which 50% of a response can be elicited (signalling, differentiation, proliferation or survival): it practically relates to the effective concentration for half-maximum response (EC50) value or affinity of the cytokine for its receptor and is typically in the 10 pMol range.

Cytokine spring

A fundamental mechanism to achieve immune homeostasis. Cells of multiple lineages secrete and consume cytokines that drive their proliferation and death. When one of the cell populations is at carrying capacity (in other words, when its expansion has plateaued), the system behaves as a cytokine spring and achieves homeostatic stability.

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Altan-Bonnet, G., Mukherjee, R. Cytokine-mediated communication: a quantitative appraisal of immune complexity. Nat Rev Immunol 19, 205–217 (2019). https://doi.org/10.1038/s41577-019-0131-x

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