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Biology and regulation of IL-2: from molecular mechanisms to human therapy

Nature Reviews Immunology volume 18, pages 648–659 (2018)Cite this article

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Abstract

IL-2 was first identified as a growth factor capable of driving the expansion of activated human T cell populations. In the more than 40 years since its discovery, a tremendous amount has been learned regarding the mechanisms that regulate the expression of both IL-2 and its cell surface receptor, its mechanisms of signalling and its range of biological actions. More recently, the mechanisms by which IL-2 regulates CD4+ T cell differentiation and function have been elucidated. IL-2 also regulates the effector and memory responses of CD8+ T cells, and the loss of IL-2 or responsiveness to IL-2 at least in part explains the exhausted phenotype that occurs during chronic viral infections and in tumour responses. These basic mechanistic studies have led to the therapeutic ability to manipulate the action of IL-2 on regulatory T (Treg) cells for the treatment of autoimmune disease and on CD8+ T cells for immunotherapy of cancer. IL-2 can have either positive or deleterious effects, and we discuss here recent ideas and approaches for manipulating the actions and overall net effects of IL-2 in disease settings, including cancer.

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Fig. 1: IL-2–IL-2 receptor structure and gene regulation.
Fig. 2: A STAT5-bound super-enhancer regulates expression of the Il2ra gene.
Fig. 3: Roles of IL-2 interactions in CD4+ T helper cell differentiation.
Fig. 4: Interactions among CD4+ T cells, Treg cells, TFH cells and TFR cells within the germinal centre.
Fig. 5: Antibodies against IL-2 or IL-2 receptor mediate actions on specific cell subsets.
Fig. 6: Engineering cytokines and receptors for optimal therapeutic activity.

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Acknowledgements

This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health.

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Nature Reviews Immunology thanks O. Boyman and T. Malek for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Laboratory of Molecular Immunology and The Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Rosanne Spolski, Peng Li & Warren J. Leonard

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All authors contributed to research and discussion of content of the article and to writing, reviewing and editing of the manuscript before submission.

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Correspondence to Warren J. Leonard.

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W.J.L. is an inventor on patents related to IL-2 partial agonists. R.S. and P.L. declare no competing interests.

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Glossary

X-linked severe combined immunodeficiency

(XSCID). A profound immunodeficiency that accounts for approximately half of all cases of SCID. It is characterized by greatly diminished numbers of T cells and natural killer cells. B cells are normal in number but are non-functional.

Super-enhancer

A cluster of transcriptional regulatory elements, often spanning an extended region, that functionally modulate gene expression as a unit.

Chromatin interaction analysis using paired-end tag sequencing

(ChIA-PET). A method for identifying pairs of regions associated with a particular protein by combining chromatin immunoprecipitation with the isolation of interacting DNA fragments.

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The use of CRISPR activation (CRISPRa) for high-throughput functional enhancer discovery with libraries of guide RNAs that tile genomic loci of interest.

Promoter capture Hi-C

The incorporation of a sequence capture step into a Hi-C protocol to enable high-resolution analysis of annotated promoters and their interacting regions from Hi-C libraries.

Chronic-smouldering forms of adult T cell leukaemia/lymphoma

As opposed to the more aggressive acute and lymphomatous forms of adult T cell leukaemia, the chronic and smouldering forms are slow-growing forms of the disease, with milder symptoms. These leukaemias are caused by human T cell lymphotropic virus type 1.

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Spolski, R., Li, P. & Leonard, W.J. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol 18, 648–659 (2018). https://doi.org/10.1038/s41577-018-0046-y

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