The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Warren J Leonard; Jian-Xin Lin; John J O'Shea

doi:10.1016/j.immuni.2019.03.028

The γ_c Family of Cytokines: Basic Biology to Therapeutic Ramifications

Immunity. 2019 Apr 16;50(4):832-850. doi: 10.1016/j.immuni.2019.03.028.

Authors

Warren J Leonard¹, Jian-Xin Lin², John J O'Shea³

Affiliations

¹ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA. Electronic address: leonardw@nhlbi.nih.gov.
² Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA. Electronic address: linjx@nhlbi.nih.gov.
³ Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Metabolic, and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1674, USA. Electronic address: osheaj@arb.niams.nih.gov.

PMID: 30995502
DOI: 10.1016/j.immuni.2019.03.028

Abstract

The common cytokine receptor γ chain, γ_c, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γ_c results in X-linked severe combined immunodeficiency in humans, and γ_c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

Publication types

Research Support, N.I.H., Intramural
Review

MeSH terms

Animals
Autoimmune Diseases / genetics
Autoimmune Diseases / immunology
Cytokines / classification*
Cytokines / genetics
Cytokines / immunology
Evolution, Molecular
Gene Expression Regulation
Genetic Therapy
Humans
Immunologic Deficiency Syndromes / immunology
Immunologic Deficiency Syndromes / therapy
Interleukin Receptor Common gamma Subunit / genetics*
Janus Kinase 3 / antagonists & inhibitors
Janus Kinases / antagonists & inhibitors
Janus Kinases / physiology
Lymphocyte Subsets / immunology
Mice
Molecular Targeted Therapy
Multigene Family / genetics
Multigene Family / immunology*
Neoplasms / genetics
Neoplasms / immunology
Protein Subunits
STAT Transcription Factors / physiology
Signal Transduction
Translational Research, Biomedical
X-Linked Combined Immunodeficiency Diseases / genetics
X-Linked Combined Immunodeficiency Diseases / immunology
X-Linked Combined Immunodeficiency Diseases / therapy

Substances

Cytokines
Interleukin Receptor Common gamma Subunit
Protein Subunits
STAT Transcription Factors
JAK3 protein, human
Janus Kinase 3
Janus Kinases