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  • Review Article
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Tolerance, not immunity, crucially depends on IL-2

Nature Reviews Immunology volume 4, pages 665–674 (2004)Cite this article

Key Points

  • Mice deficient in interleukin-2 (IL-2), the α-chain of the IL-2 receptor (Il-2Rα) or the the β-chain of the IL-2 receptor (IL-2Rβ) are characterized by hyperproliferation and hyperactivation of peripheral T cells, together with haemolytic anaemia and multi-organ autoimmune disease, which results in death by 4 to 12 weeks of age. This observation indicates that the main role of IL-2 is to control peripheral T-cell tolerance.

  • IL-2-, IL-2Rα- and IL-2Rβ-deficient mice have a greatly reduced number of CD4+CD25+ regulatory T (TReg) cells. Correcting TReg-cell production in such mice is sufficient to prevent the onset of lethal autoimmune disease, thereby directly showing that the main role for IL-2 in peripheral T-cell tolerance is the production of TReg cells.

  • IL-2 contributes to TReg-cell production during thymic development and in peripheral lymphoid tissues. One role for IL-2 seems to be as a growth factor for TReg cells.

  • IL-2 is essential for T-cell responses in vitro. Both T-cell clonal expansion and differentiation into effector cells do not occur appropriately in the absence of signalling through the IL-2R.

  • Remarkably, both IL-2-deficient and IL-2R-deficient mice mount effective immune responses in vivo. These relatively normal immune responses are not secondary to autoimmune disease, because effective immune responses occur when disease is prevented in such mice.

  • IL-2 does, however, contribute to T-cell immunity in vivo. IL-2 seems to be more important during the later stages of immune responses. It has been shown to contribute to the type or magnitude of effector cell that is produced and to be involved in the migration or proliferation of effector cells in non-lymphoid tissue.

  • There are distinct requirements for IL-2 in vitro and in vivo. This is probably because IL-2 is the dominant cytokine for T-cell growth and effector-cell differentiation in vitro, whereas there is redundancy in these activities in vivo. The nature of such redundant signals remains to be defined.

  • Clinical applications that target IL-2 and/or the IL-2R might not be synonymous with blocking or enhancing T-cell immunity. TReg cells might also be affected by these types of therapeutic strategy.

Abstract

Interleukin-2 (IL-2) was identified based on its potent T-cell growth-factor activity and is widely considered to be a key cytokine in T-cell-dependent immune responses. However, the main non-redundant activity of this cytokine centres on the regulation of T-cell tolerance, and recent studies indicate that a failure in the production of CD4+CD25+ regulatory T cells is the underlying cause of autoimmunity in the absence of IL-2. In marked contrast to the importance of IL-2 in peripheral T-cell tolerance, T-cell immunity is readily elicited to various agents in the absence of IL-2 in vivo. Here, we discuss these findings and, in particular, the action of IL-2 on regulatory T cells and effector cells, and the targeting of IL-2 and/or the IL-2 receptor in clinical settings.

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Figure 1: IL-2 receptor signalling.
Figure 2: IL-2 is a growth factor for TReg cells.
Figure 3: Models of the cellular source of IL-2 for TReg cells.
Figure 4: Signal 3 is essential for production of an efficient T-cell response.

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Acknowledgements

T.R.M. is supported by grants from the National Institutes of Health, United States.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Thomas R. Malek & Allison L. Bayer

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  1. Thomas R. Malek
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Correspondence to Thomas R. Malek.

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DATABASES

Entrez Gene

4-1BB

BCL-2

CD4

CD8

CD27

CD28

CD40L

CD62L

CD80

CD86

CTLA4

FAS

FOXP3

γc

IL-2

IL-2Rα

IL-2Rβ

IL-15

IL-15R

OX40

STAT5

TNF

transforming growth factor-β

Glossary

FOUR-BUNDLE α-HELICAL CYTOKINE

A cytokine that contains four regions of α-helical structure, such as interleukin-2 and other members of the common cytokine-receptor γ-chain family of cytokines.

LYMPHOPROLIFERATION

The in vivo growth and clonal expansion of lymphocytes.

CD4+CD25+ REGULATORY T (TReg) CELLS

A subset of lymphocytes that suppress autoreactive T cells that escape negative selection in the thymus.

PARACRINE

The production of a soluble effector that functions on target cells that are distinct from the cell that produced it.

ATHYMIC

Lacking a thymus.

PRECURSOR FREQUENCY

The initial number of antigen-specific lymphocytes relative to the total number that respond and clonally expand to a particular antigen during an immune response.

SUPERANTIGENS

Microbial products that activate T cells by crosslinking cell-surface-expressed T-cell receptors. They achieve this by binding to the Vβ region of a T-cell receptor; however, only particular Vβ regions are favoured.

ALLO-SPECIFIC CTL

An effector T-cell that responds to genetically distinct individuals of the same species. This response results in the lysis of cells that show cell-surface expression of the appropriate alloantigen, which is usually encoded by MHC class I genes.

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Malek, T., Bayer, A. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 4, 665–674 (2004). https://doi.org/10.1038/nri1435

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