Cytokine-mediated communication: a quantitative appraisal of immune complexity

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.

Figure 1 |. Three modes of cytokine-mediated cell-to-cell communication.

Cells of the immune system communicate through the exchange of secreted cytokines. Depending on the spatial location and identity of the cytokine-consuming cell, such communication can be autocrine (signaling to self), paracrine (signaling to neighboring cells) or endocrine (signaling globally through the circulation). The key parameters that determine the signaling mode are the rate of cytokine production (R_production) and the rate of cytokine consumption (R_consumption). Recent quantitative studies in systems immunology have begun to clarify how cells switch from one mode of signaling to another.

Figure 2 |. The rate of cytokine consumption affects signaling mode during an immune response.

The characteristic length scale (λcytokine) at which cell-to-cell communication by a given cytokine takes place is highly tunable based on molecular and cellular parameters. At the start of an immune response, when the number of cytokine-consuming cells is low, λcytokine can be in the range of 100 μm, which enables paracrine signalling. As the immune response progresses, the number of cytokine-consuming cells increases and these may cluster around cytokine-producing cells, which decreases λcytokine to only a few μm. As a result, autocrine signaling becomes dominant. [Au:OK?] [Yes]

Figure 3 |. Variable confinement of cytokine-mediated communication within the T cell immunological synapse.

a | For a tight-sealed immunological synapse between a CD4⁺ T helper cell and antigen-presenting cell (APC), there are differential patterns of cytokine secretion. In this example, IFNγ is directionally released into the immunological synapse to mediate short-range communication, whereas tumour necrosis factor (TNF) is more multidirectional in its secretion pattern and thus mediates longer-range communication. b | For a leaky immunological synapse, even those cytokines such as IFNγ that are released into the synapse^, can be involved in longer-range multicellular interactions as a result of a limited consumption rate by the synapsed APC. This is known as the ‘two-pathway’ model of cytokine secretion. [Au:OK?] [Actually, ‘a’ is the ‘Two-pathway’ model, whereas ‘b’ is called the ‘leaky synaptic’ model.]

Figure 4 |. Homeostasis by cytokine competition.

a | Erythrocyte homeostasis. A drop of partial oxygen pressure in the blood (hypoxia) is detected by kidney cells (through the activation of hypoxia-induced factor 1 (HIF1)), which triggers their secretion of erythropoietin (EPO). EPO circulates to the bone marrow to induce the proliferation of erythrocyte precursors, which restores oxygen partial pressure. b | Platelet homeostasis. The rapid decrease in number of circulating platelets (thrombocytopenia) during trauma results in the serum accumulation of constitutively expressed thrombopoietin (THPO), which signals to bone marrow megakaryocytes for platelet release, thereby restoring haemostasis. c | Naive T cell homeostasis. Innate lymphoid cells (ILCs) are present at low frequencies in lymphoid organs compared with T cells but unlike T cells they do not adapt their response to IL-7 by downregulating expression of the IL-7 receptor α-subunit (IL-7Rα). The sustained consumption of IL-7 by ILCs limits the spatial extent and overall availability of IL-7 in lymph nodes. d | Tissue homeostasis. Activated effector T cells secrete IL-2, which drives their proliferation and upregulation of IL-2 receptor (IL-2R) expression. Regulatory T (T_reg) cells constitutively express IL-2R and consume IL-2, which upregulates their inhibitory functions. Competition between the production and consumption of IL-2 determines the balance between immune activation and immune tolerance. [Au:OK?] [Yes]