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  • Review Article
  • Published:

Cytokines and immunodeficiency diseases

Nature Reviews Immunology volume 1, pages 200–208 (2001)Cite this article

Key Points

  • Mutations in the common cytokine receptor γ-chain (γc) cause X-linked severe combined immunodeficiency disease (XSCID).

  • Because Janus-activated kinase 3 (JAK3) associates with γc, we predicted that mutations in JAK3 cause autosomal-recessive SCID. Indeed, this was confirmed.

  • Mutations in the interleukin-7 receptor (IL-7R) gene causes T−B+NK+ SCID.

  • Mice that lack various Jaks and Stats (signal transducers and activators of transcription) have major immunological and non-immunological defects.

  • Most of the cytokines we have discussed are type I cytokines; interferons and IL-10 are examples of type II cytokines.

Abstract

Severe combined immunodeficiency disease (SCID) refers to a spectrum of inherited immunodeficiencies that together represent the most severe forms of primary immunodeficiency in humans. Recent work has shown that many of these diseases, as well as other forms of immunodeficiency, result from defects in cytokine signalling pathways. Such defects can prevent normal development of lymphoid lineages and/or compromise cytokine signalling by these cells. These natural 'experiments' in human genetics have shown the non-redundant role for several cytokines or cytokine signalling molecules. Moreover, a comparison of the phenotypes of humans with SCID to analogous mouse-knockout models has shown not only expected similarities, but also unexpected differences in cytokine signalling between humans and mice.

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Figure 1: Actions of cytokines whose receptors share γc.
Figure 2: Signalling by the JAK/STAT pathway for a typical type I cytokine.

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Authors and Affiliations

  1. Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892-1674, Maryland, USA

    Warren J. Leonard

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  1. Warren J. Leonard
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Supplementary information

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DATABASES

LocusLink

Bcl-2

cardiotrophin 1

CDk6

ciliary neurotrophic factor

CIS

c-kit

cyclin D2

cyclin D3

epidermal growth factor

erythropoietin

γc

gp130

IFN-γ

IFNGR1

IFNGR2

IL-2

IL-2R

IL2RG

IL-3

IL-4

IL-6

IL-7

IL-9

IL-10

IL-11

IL12B

IL12RB1

IL-13

IL-15

IL-21

ISGF3

JAK1–3

leukaemia-inhibitory factor

oncostatin M

Pim-1

SOCS1

SSI-1

STAT1–4

STAT5A

STAT5B

STAT6

TYK2

OMIM

XSCID

FURTHER INFORMATION

Cytokines

Cytokines as mediators of disease

Cytokine receptors

Immune deficiency: severe combined immune deficiency

Interleukins

Signal transduction pathways in development: the JAK/STAT pathway

JAK3base

X-Linked SCID Mutation Database

Glossary

NATURAL KILLER CELLS

(NK cells). Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they have a broader role in host defence against invading pathogens.

XSCID

X-linked severe combined immunodeficiency disease. This is a profound immunodeficiency that accounts for approximately half of the cases of SCID. It is characterized by an absence of T cells and natural killer cells. B cells are normal in number but are non-functional.

COMMON CYTOKINE RECEPTOR γ-CHAIN

(γc). A type I cytokine receptor chain that is shared by the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

JAK

Janus-activated kinase. There are four JAKs — JAK1, JAK2, JAK3 and TYK2 — which are activated by cytokines and interferons, inducing the phosphorylation of the cytokine/interferon receptors and other cellular substrates, including STAT proteins.

STAT

Signal transducer and activator of transcription. These are proteins that are recruited to cytokine and interferon receptors following ligand binding to the receptor. STAT proteins are 'activated' by tyrosine phosphorylation so that they can form dimers and translocate to the nucleus, where they function as transcription factors.

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Leonard, W. Cytokines and immunodeficiency diseases. Nat Rev Immunol 1, 200–208 (2001). https://doi.org/10.1038/35105066

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  • DOI: https://doi.org/10.1038/35105066

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