Interleukin 2
| Interleukin 2 | |||||||||||
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 Human Interleukin 2 crystal structure | |||||||||||
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| Symbols | IL2 ; IL-2; TCGF; lymphokine | ||||||||||
| External IDs | Template:OMIM5 Template:MGI HomoloGene: 488 | ||||||||||
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| Species | Human | Mouse | |||||||||
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Overview
Interleukin-2 (IL-2) is an interleukin, a type of cytokine immune system signalling molecule, that is instrumental in the body's natural response to microbial infection and in discriminating between foreign (nonself) and self. IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes, the cells that are responsible for immunity.
Discovery and characterization
The IL-2 molecule was first characterized as a variably glycosylated 15,500 Dalton protein capable of supporting long-term T lymphocyte (T cell) proliferation,[1] and was first purified to homogeneity by immunoaffinity chromatography.[2] The IL-2 molecule was also the first interleukin found to be encoded by a complementary DNA (cDNA),[3] and to mediate its effects via a specific IL-2 receptor.[4] Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, gene and receptor to be discovered. It was designated number 2 because data at the time indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells)[5][6]
IL-2 signaling pathway
Interleukin-2 belongs to a family of cytokines, which includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor complex consisting of IL-2 specific IL-2 receptor alpha (CD25), IL-2 receptor beta (CD122) and a common gamma chain (γc), which is shared by all members of this family of cytokines. Binding of IL-2 activates the Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules. More comprehensive details are provided in NetPath.
Physiology and immunology
IL-2 is normally produced by the body during an immune response.[7][8] When environmental substances (molecules or microbes) gain access to the body, these substances (termed antigens) are recognized as foreign by antigen receptors that are expressed on the surface of lymphocytes. Antigen binding to the T cell receptor (TCR) stimulates the secretion of IL-2, and the expression of IL-2 receptors IL-2R. The IL-2/IL-2R interaction then stimulates the growth, differentiation and survival of antigen-selected cytotoxic T cells via the activation of the expression of specific genes.[9][10][11] As such, IL-2 is necessary for the development of T cell immunologic memory, one of the unique characteristics of the immune system, which depends upon the expansion of the number and function of antigen-selected T cell clones.
IL-2 is also necessary during T cell development in the thymus for the maturation of a unique subset of T cells that are termed regulatory T cells (T-regs).[12][13][14] After exiting from the thymus, T-Regs function to prevent other T cells from recognizing and reacting against "self antigens", which could result in "autoimmunity". T-Regs do so by preventing the responding cells from producing IL-2[13] Thus, IL-2 is required to discriminate between self and non-self, another one of the unique characteristics of the immune system.
IL-2 has been found to be similar to IL-15 in terms of function.[15] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[15][16] The primary differences between IL-2 and IL-15 are found in adaptive immune responses. For example, IL-2 participates in maintenance of T-Regs and reduces self-reactive T cells. On the other hand, IL-15 is necessary for maintaining highly specific T cell responses by supporting survival of CD8 memory T cells. The differences in function in these two cytokines stem from the signal transduction mechanisms and differing receptors.
Uses in medicine
A recombinant form of IL-2 is manufactured by Chiron Corporation with the brand name Proleukin. It has been approved by the Food and Drug Administration (FDA) for the treatment of cancers (malignant melanoma, renal cell cancer), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines. The role of IL-2 in HIV therapy remains to be fully determined.
Many of the immunsuppressive drugs used in the treatment of autoimmune diseases such as corticosteroids, and organ transplant rejection (cyclosporine, tacrolimus) work by inhibiting the production of IL-2 by antigen-activated T cells. Others (Rapamycin) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells.
References
- ↑ Robb R, Smith KA (1981). "Heterogeneity of human T-cell growth factor(s) due to variable glycosylation". Mol. Immunol. 18: 1087–94. PMID 6977702.
- ↑ Smith KA, Favata MF, Oroszlan S (1983). "Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics". J. Immunol. 131: 1808. PMID 6352804.
- ↑ Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J (1983). "Structure and expression of a cloned cDNA for human interleukin-2". Nature. 302 (5906): 305. PMID 6403867.
- ↑ Robb RJ, Munck A, Smith KA (1981). "T cell growth factor receptors. Quantitation, specificity, and biological relevance". J. Exp. Med. 154 (5): 1455–74. PMID 6975347.
- ↑ Smith KA, Lachman LB, Oppenheim JJ, Favata MF (1980). "The functional relationship of the interleukins". J. Exp. Med. 151 (6): 1551–6. PMID 6770028.
- ↑ Smith KA, Gilbride KJ, Favata MF (1980). "Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells". Nature. 287 (5785): 853–5. PMID 6776414.
- ↑ Cantrell DA, Smith KA (1984). "The interleukin-2 T-cell system: a new cell growth model". Science. 224: 1312–6. PMID 6427923.
- ↑ Smith KA (1988). "Interleukin-2: inception, impact, and implications". Science. 240: 1169–76. PMID 3131876.
- ↑ Stern J, Smith KA (1986). "Interleukin-2 induction of T-cell G1 progression and c-myb expression". Science. 233: 203–6. PMID 3523754.
- ↑ Beadling C, Johnson KW, Smith KA (1993). "Isolation of interleukin 2-induced immediate-early genes". Proc. Nat. Acad. Sci. U.S.A. 90: 2719–23. PMID 7681987.
- ↑ }Beadling CB, Smith KA (2002). "DNA array analysis of interleukin-2-regulated immediate/early genes". Med. Immunol. 1: 2. PMID 12459040.
- ↑ Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995). "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases". J. Immunol. 155: 1151–64. PMID 7636184.
- ↑ 13.0 13.1 Thornton AM, Shevach EM (1998). "CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production". J. Exp. Med. 188: 287–96. PMID 9670041.
- ↑ Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004). "Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function". J. Immunol. 172: 6519–23. PMID 15153463.
- ↑ 15.0 15.1 Waldmann TA (2006). "The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design". Nature Rev. Immun. 6 (8): 595–601. PMID 16868550.
- ↑ Waldmann TA, Tagaya Y (1999). "The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens". Annu. Rev. Immunol. 17: 19–49. PMID 10358752.