Immunology: Chapter 9 — Cytokines as a network

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9.1 Groups and behaviour #

9.1.1 Functional groups, and how they signal #

Inflammatory cytokines — IL-1, TNF, and IL-6 — come from activated macrophages and dendritic cells. They activate endothelium, recruit leucocytes, cause fever, and induce the acute-phase response. Local, they are defence; systemic, they are shock. Type I interferons, many IFN-α species and one main IFN-β, are made by infected cells and in quantity by plasmacytoid dendritic cells. Neighbours enter an antiviral state: PKR slows translation on double-stranded RNA, OAS activates RNase L, and Mx proteins interfere with viral assembly. MHC class I rises and NK cells and dendritic cells are activated. Among growth and survival cytokines, IL-7 maintains lymphocytes, IL-2 drives activated T cells and is required by regulatory T cells, and IL-15 maintains NK cells and memory CD8 cells. The receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 share the common γ chain, whose loss is X-linked SCID. IL-13 does not use that chain. The polarising cytokines were named with the helpers that make them: IL-12 and IFN-γ, IL-4 with IL-5 and IL-13, IL-17 and IL-22, IL-21, and IL-10 with TGF-β. Most of these receptors use JAK kinases and STAT transcription factors. IFN-γ uses JAK1, JAK2, and STAT1; IL-6 uses STAT3; IL-4 uses STAT6. Loss of STAT1, the IFN-γ receptor, or the IL-12 receptor selectively disables defence against intracellular bacteria, especially mycobacteria, while antibody can remain.

9.1.2 Pleiotropy, redundancy, antagonism, and chemokines #

Pleiotropy is one cytokine with several jobs. IL-6 induces acute-phase proteins, contributes to fever, supports antibody, and, with other signals, favours Th17 cells. TNF activates endothelium, causes fever, and helps maintain granulomas. Redundancy is several cytokines sharing a job: IL-1 and TNF both activate endothelium and both cause fever. Antagonism makes the choice: IFN-γ blocks Th2 differentiation, IL-4 blocks Th1, and IL-10 and TGF-β dampen inflammatory cytokines. Chemokines are addresses. CXCL8 brings neutrophils, CCL2 brings monocytes, CCL19 and CCL21 through CCR7 bring naive T cells and mature dendritic cells into the paracortex, and CXCL13 through CXCR5 brings B cells and T follicular helpers into follicles.

9.1.3 Cytokine storm #

A cytokine storm is loss of containment. TNF, IL-1, IL-6, IFN-γ, and others rise in the blood and induce one another, so feedback is positive. Endothelium leaks, pressure falls, coagulation is disordered, and organs fail. The trigger may be a superantigen firing many T cells, an infection whose innate response never comes under control, or a therapy that activates many T cells together. The concept is that loop in the circulation. At a focus of infection the same molecules are ordinary defence.

9.2 Key terms, summary, and self-check #

Key terms. IL-1; TNF; IL-6; type I interferon; IL-2; IL-7; common γ chain; pleiotropy; redundancy; JAK–STAT; CXCL8; CCR7; CXCL13; cytokine storm.

Summary. Inflammatory cytokines, type I interferons, lymphocyte growth factors, and polarising cytokines form a network in which one cytokine has many targets and several cytokines share a target. Chemokines place the cells. Most receptors act through a JAK–STAT pair, so one receptor defect can remove an entire arm. A cytokine storm is that network in positive feedback in the blood.

Self-check.

1. Place IL-1, IFN-α, IL-2, and IL-4 each in a functional group and name one job of each.

2. Give one example of pleiotropy and one of redundancy.

3. Which chemokine–receptor pairs bring a naive T cell into the paracortex and a B cell into a follicle?

4. Why can a superantigen release far more cytokine than one conventional peptide?

5. What makes a cytokine response a storm rather than local inflammation? Answer in terms of feedback and place.