Key Points
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Interleukin-2 (IL-2) and IL-15 have both similar and contrasting functional roles in the life and death of lymphocytes.
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The heterotrimeric receptors for these cytokines have two subunits in common: IL-2/15Rβ (also known as the IL-2 receptor β-chain (IL-2Rβ) and IL-15Rβ); and the common cytokine-receptor γ-chain (γc). The two cytokine receptors also have distinct α-subunits.
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In many adaptive immune responses, IL-2 and IL-15 have distinct, and often competing, actions. IL-2 has a role in activation-induced cell death and in maintenance of regulatory T cells. In this way, it is involved in the elimination of self-reactive T cells, which if left unregulated could lead to the development of autoimmune diseases. By contrast, IL-15 is pivotal in the maintenance of long-lasting, high-avidity CD8+ memory T cells that are involved in the elimination of invading pathogens, thereby protecting the host against infection.
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IL-2 is a secreted cytokine and binds pre-formed heterotrimeric receptors on the surface of activated cells. By contrast, IL-15 is mainly membrane bound, and it induces signalling in the context of cell–cell contact, at the immunological synapse. The unique subunit of the IL-15R, IL-15Rα, presents IL-15 in trans to neighbouring natural killer (NK) cells and CD8+ T cells.
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IL-15 activates T cells and NK cells and has a role in persistence of CD8+ memory T cells. It therefore might be better than IL-2 for the treatment of cancer and as a component of molecular vaccines against infectious diseases.
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Because IL-15 activates tumour-necrosis-factor expression and facilitates memory CD8+ T-cell maintenance, dysregulation of IL-15 is associated with a range of autoimmune inflammatory diseases. Therapeutic strategies that inhibit the actions of IL-15 are being developed for the treatment of T-cell-mediated autoimmune inflammatory diseases.
Abstract
Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.
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Acknowledgements
This research was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health (USA).
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The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design Nature Reviews Immunology 6, 595–601 (2006); doi:10.1038/nri1901
Together with the US government, Thomas Waldmann holds patent number 5,833,983, entitled Interleukin-2 receptor (IL-2Rβ) and application thereof. This patent provides royalty payments.
Glossary
- Activation-induced cell death
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(AICD). A process by which fully activated T cells undergo programmed cell death through engagement of cell-surface-expressed death receptors such as CD95 (also known as FAS) or the tumour-necrosis-factor receptor.
- CD4+CD25+ regulatory T cell
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(TReg cell). A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by expression of the α-chain of the interleukin-2 receptor (also known as CD25) and the transcription factor forkhead box P3 (FOXP3).
- Intestinal intraepithelial lymphocyte
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A T cell that resides in the basolateral side of the intestinal epithelium. These cells express either an αβ-T-cell receptor (TCR) or a γδ-TCR, as well as a CD8αα homodimer. This is in contrast to most conventional CD8+ T cells, which express a CD8αβ heterodimer. CD8αα is a ligand for the non-classical MHC class I molecule thymus leukaemia antigen (TL), which is expressed by the intestinal epithelium.
- Trans-presentation
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A process by which the α-chain of the interleukin-15 (IL-15) receptor (IL-15Rα) presents active IL-15 in trans to opposing cells expressing a complex (with an intermediate affinity for IL-15) that contains the β-chain IL-2/15Rβ and the common cytokine-receptor γ-chain (γc), thereby transducing a signal.
- Fluorescence resonance energy transfer
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(FRET). A technique that is used to measure protein–protein interactions either by microscopy or flow cytometry. Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluorophores. Such transfer can only occur if proteins physically interact.
- Immunological synapse
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A region that can form between two cells of the immune system in close contact. The name derives from similarities to the synapses that occur in the nervous system. The immunological synapse refers to the interaction between a T cell or natural killer cell and an antigen-presenting cell. This interface involves adhesion molecules, as well as antigen receptors and cytokine receptors.
- Delayed-type hypersensitivity
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A cellular immune response to antigen that develops over 24–72 hours. It involves the infiltration of T cells and monocytes, and it depends on the production of T-helper-1 cytokines.
- Collagen-induced arthritis
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An experimental model of rheumatoid arthritis. Arthritis is induced by immunization of susceptible animals with type II collagen.
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Waldmann, T. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6, 595–601 (2006). https://doi.org/10.1038/nri1901
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DOI: https://doi.org/10.1038/nri1901
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