Interleukin 2
Interleukin-2 (IL-2) is an interleukin, a type of cytokine immune system signaling molecule, that is instrumental in the body's natural response to microbial infection and in discriminating between foreign (non-self) 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
IL-2 was the first cytokine to be discovered. What is now known as IL-2 was first reported in the journal Nature in 1965 as a soluble mitogenic activity in the culture media of mixed leukocytes.[5] T cell growth factor (TCGF) was first characterized as a soluble activity in lymphocyte conditioned media that supported the long-term proliferation of lymphocytes in culture. Subsequent biochemical characterization of TCGF by the same group revealed it to be a variably glycosylated 15,500 Dalton protein,[6] and was first purified to homogeneity by immunoaffinity chromatography.[7] This discovery of the first soluble "hormone-like" mediator of the immune system galvanized the field of immunology as the important role of cytokines had not been previously demonstrated. The IL-2 molecule was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library,[8] and was subsequently shown to mediate its effects via a specific IL-2 receptor.[9] 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).[10][11]
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.[12][13] 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.[14][15][16] 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).[17][18][19] 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[18] 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.[20] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[20][21] 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
The World Reference Standard for IL-2 is produced by the National Institute of Biological Standards and Control in the UK. A recombinant form of IL-2 for clinical use 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 immunosuppressive 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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000109471 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027720 – Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ Robb R, Smith KA (1981). "Heterogeneity of human T-cell growth factor(s) due to variable glycosylation". Mol. Immunol. 18: 1087–94. doi:10.1016/0161-5890(81)90024-9. PMID 6977702.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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. doi:10.1038/302305a0. PMID 6403867.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Cantrell DA, Smith KA (1984). "The interleukin-2 T-cell system: a new cell growth model". Science. 224: 1312–6. doi:10.1126/science.6427923. PMID 6427923.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ }Beadling CB, Smith KA (2002). "DNA array analysis of interleukin-2-regulated immediate/early genes". Med. Immunol. 1: 2. doi:10.1186/1476-9433-1-2. PMID 12459040.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b 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. doi:10.1084/jem.188.2.287. PMID 9670041.
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