The role of interleukin-2 during homeostasis and activation of the immune system

Key Points

  • Under steady-state resting conditions, interleukin-2 (IL-2) is mainly produced by activated CD4+ T cells in secondary lymphoid organs. The secreted IL-2 is then consumed at the same site by cells that express the IL-2 receptor subunit CD25 (also known as IL-2Rα), notably regulatory T (TReg) cells. During an immune response, activated antigen-specific CD4+ and CD8+ T cells produce large amounts of IL-2, which is then consumed by CD25+ effector T cells and TReg cells.

  • The strength and duration of the IL-2 signal controls both the primary and secondary expansion of antigen-specific CD8+ T cell populations. Suboptimal IL-2 signals during priming lead to reduced primary expansion and severely impaired secondary expansion, whereas exposure to prolonged, strong IL-2 signals during priming generates short-lived terminally differentiated effector CD8+ T cells.

  • IL-2 signals act via signal transducer and activator of transcription 5 (STAT5) and influence the differentiation of T helper (TH) cell subsets (including TH1, TH2 and TH17 cells) as well as the homeostasis of TReg cells. Moreover, similarly to the case of effector CD8+ T cells, strong IL-2 signals drive antigen-specific CD4+ T cells to become short-lived terminally differentiated effector T cells; conversely, low-level IL-2 signals allow effector CD4+ T cells to differentiate into follicular helper or central memory T cells.

  • Activated dendritic cells (DCs) express CD25 on their cell surface for binding either T cell- or DC-derived IL-2, in order to present IL-2 in trans to adjacent effector T cells. This mechanism presumably operates very early during T cell stimulation, before the responding T cells start to express CD25.

  • IL-2 is produced chiefly by activated T cells in secondary lymphoid organs, where it is consumed by these cells and other CD25+ cells, including TReg cells. In addition to cells of the immune system, non-immune cells express CD25 molecules, and these CD25+ cells might contribute to the control of IL-2 homeostasis in peripheral organs.

  • The ability of IL-2 to activate both TReg cells and cytotoxic lymphocytes might be circumvented by using low-dose IL-2 immunotherapy to increase only TReg cell numbers in autoimmunity, chronic inflammatory conditions and graft rejection; conversely, high-dose IL-2 administration might serve to expand cytotoxic lymphocyte populations for the treatment of metastatic cancer. An alternative approach for selective IL-2 immunotherapy would be to use improved IL-2 formulations, such as IL-2 bound to particular IL-2-specific monoclonal antibodies, or IL-2 muteins with increased affinity for CD25 or CD122 (also known as IL-2Rβ).

Abstract

Interleukin-2 (IL-2) signals influence various lymphocyte subsets during differentiation, immune responses and homeostasis. As discussed in this Review, stimulation with IL-2 is crucial for the maintenance of regulatory T (TReg) cells and for the differentiation of CD4+ T cells into defined effector T cell subsets following antigen-mediated activation. For CD8+ T cells, IL-2 signals optimize both effector T cell generation and differentiation into memory cells. IL-2 is presented in soluble form or bound to dendritic cells and the extracellular matrix. Use of IL-2 — either alone or in complex with particular neutralizing IL-2-specific antibodies — can amplify CD8+ T cell responses or induce the expansion of the TReg cell population, thus favouring either immune stimulation or suppression.

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Figure 1: IL-2 homeostasis in steady-state conditions and during an immune response.
Figure 2: The IL-2 receptor system and IL-2 signalling.
Figure 3: The role of IL-2 signalling in CD8+ T cell responses following acute infection by pathogens.
Figure 4: The role of IL-2 signals in the differentiation and survival of CD4+ T helper cell subsets and TReg cells.
Figure 5: The impact of IL-2 signals on the differentiation of effector and follicular helper CD4+ T cells.

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Acknowledgements

We thank the members of the Boyman and Sprent laboratories for helpful discussions. This work was supported by Swiss National Science Foundation grant PP00P3-128421 (to O.B.), Swiss Cancer League grant KFS-02672-08-2010 (to O.B.) and a grant from the Fonds zur Förderung des Akademischen Nachwuchses of the Zürcher Universitätsverein (to O.B.), as well as by Juvenile Diabetes Research Foundation grant 1-2010-166 (to J.S.), grants from the Australian National Health and Medical Research Council (to J.S.) and World Class University (National Research Foundation of Korea) grants (to J.S.).

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Correspondence to Onur Boyman.

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Onur Boyman and Jonathan Sprent are shareholders of Nascent Biologics Inc.

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Glossary

Central memory T cells

Antigen-experienced resting T cells that express cell-surface receptors that are required for homing to secondary lymphoid organs. These cells are generally long-lived and can serve as the precursors for effector T cells during recall responses.

Activation-induced cell death

A process by which activated T cells undergo cell death through the engagement of death receptors (such as FAS or the TNF receptor) or the production of reactive oxygen species.

Trans-endocytosis

The process by which a tightly associated receptor–ligand complex induces invagination of the plasma membrane and internalization of the complex into the receptor-bearing cell to form a membrane-limited transport vesicle.

Lipid rafts

Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein organization.

Germinal centres

Lymphoid structures that arise in B cell follicles after immunization with, or exposure to, a T cell-dependent antigen. They are specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Class switching

A region-specific genetic recombination process that occurs in antigen-activated B cells. This recombination occurs between switch-region DNA sequences and results in a change in the class of antibody that is produced — from IgM to either IgG, IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of these antibody classes to activate the appropriate downstream effector mechanisms.

Extravasation

A cellular process in which circulating leukocytes bind to and migrate through the endothelium into the underlying tissue.

Non-obese diabetic mice

(NOD mice). NOD mice spontaneously develop type 1 diabetes mellitus as a result of the destruction of pancreatic β-islet cells by autoreactive T cells.

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Boyman, O., Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12, 180–190 (2012). https://doi.org/10.1038/nri3156

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