Interleukin 2
Interleukin 2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of 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.
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History [edit]
IL-2, a soluble hormone-like mediator of the immune system, was the first interleukin molecule to be identified and characterized.[1][2][3][4]
A soluble activity that was found mitogenic for lymphocytes was first described simultaneously by Shinpei Kasakura and Louis Lowenstein,[5] plus Julius Gordon and Lloyd MacLean,[6] at McGill University in 1965 in the culture media of mixed leukocytes and named Blastogenic Factor (BF). The publication of this discovery in Nature was the first indication that the immune system might be regulated by soluble factors, other than immunoglobulins, and galvanized the field into looking for and further characterizing these entities. Between 1965 and the mid-1970s myriad soluble "activities", each given a different name, were reported in the media conditioned by leukocytes in culture. However, the molecular nature of these "activities" remained obscure until the work of Kendall Smith and his team at Dartmouth Medical School.
Smith's group created the first long-term antigen-specific cytotoxic T cell lines,[7] and then the first monoclonal functional T cells.[8] They then used these cloned T cell lines as target cells in developing a rapid, quantitative assay for the activity that they named T cell growth factor (TCGF).[9] They then used this new bioassay to purify the molecule responsible for the TCGF activity,[3] and raised monoclonal antibodies reactive with it, which were then used to purify the molecule to homogeneity in milligram amounts, a first for this new class of molecules.[4]
Smith's group also showed TCGF to be the first cytokine to mediate its effects via a specific IL-2 receptor,[10] and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library by Tadatsugu Taniguchi's group.[11] Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, receptor, and gene to be discovered. It was designated the number 2 interleukin because Smith's data indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells).[1][2] These data served as the scientific rationale for the creation of the interleukin nomenclature, anticipating that more molecules would be discovered. Now, in 2012, there are 37 interleukin molecules.
After the biochemical biological and genetic characteristics of IL-2 became known, Shinpei Kasakura's group performed a series of experiments defining BF almost twenty years after its first description. He was able to show that BF was distinct from IL-2, B cell growth factor and IL-1.[12] The major distinguishing characteristic was that BF was mitogenic for unstimulated lymphocytes, whereas IL-2 mitogenic activity required prior antigenic activation to stimulate the expression of IL-2Rs. Thus, BF was probably equivalent to IL-15, which was not discovered until three years later.
Signaling pathway [edit]
Subsequently, IL-2 was discovered to be a member of a family of cytokines, which also 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 cytokine receptor.
Function [edit]
IL-2 is necessary for the growth, proliferation, and differentiation of T cells to become 'effector' T cells. IL-2 is normally produced by T cells during an immune response.[13][14] 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-specific CD4+ T cells and CD8+ T cells[15][16][17] As such, IL-2 is necessary for the development of T cell immunologic memory, 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 subset of T cells that are termed regulatory T cells (T-regs).[18][19][20] 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. Also, because T-Reg cells constitutively express IL-2 receptors, they bind, internalize and degrade IL-2, thereby depriving neighboring effector T cells of IL-2. Thus, IL-2 is required to discriminate between self and non-self, one of the other hallmarks of the immune system.
IL-15 was found to be similar to IL-2.[21] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[22] The primary differences between IL-2 and IL-15 are found in adaptive immune responses. For example, IL-2 is necessary for adaptive immunity to foreign pathogens, as it is the basis for the development of immunological memory. On the other hand, IL-15 is necessary for maintaining highly specific T cell responses by supporting the survival of CD8 memory T cells
Disease [edit]
IL-2 has been linked to different diseases.[citation needed]
Immunotherapy [edit]
IL-2 has been tested in many clinical trials as an immunotherapy for the treatment of cancers, chronic viral infections and as adjuvants for vaccines.
A recombinant form of human IL-2 for clinical use is manufactured by Prometheus Laboratories, Inc. 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) in large intermittent toxic doses, and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines. The use of large, toxic doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, has been found recently to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials. However, that does not mean that the drug is ineffective in improving T-cell count. Many persons who underwent IL-2 therapy enjoyed dramatic improvement in T-cell count, as well as overall health. But the FDA determined that the risks and costs (experience of side-effects) outweighed those benefits.[citation needed] A recent study in which post-chemotherapy, stage IV cancer patients were given a non-toxic, lower dose of IL-2 in combination with 13-cis retinoic acid showed remarkable improvement in five-year survival rates.[23]
IL-2 and IL-2 receptor blockade as immunosuppression [edit]
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and the suppression of graft rejection, such as corticosteroids, cyclosporin, and tacrolimus work by inhibiting the production of IL-2 by antigen-activated T cells. Others (sirolimus) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells. These immunosuppressive drugs have been essential for the widespread use of organ transplants in medicine today. Without them, organs transplanted between unrelated individuals would be universally rejected.
References [edit]
- ^ a b Smith KA, Lachman LB, Oppenheim JJ, Favata MF (June 1980). "The functional relationship of the interleukins". J. Exp. Med. 151 (6): 1551–6. doi:10.1084/jem.151.6.1551. PMC 2185867. PMID 6770028.
- ^ a b Smith KA, Gilbride KJ, Favata MF (October 1980). "Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells". Nature 287 (5785): 853–5. doi:10.1038/287853a0. PMID 6776414.
- ^ a b Robb RJ, Smith KA (December 1981). "Heterogeneity of human T-cell growth factor(s) due to variable glycosylation". Mol. Immunol. 18 (12): 1087–94. doi:10.1016/0161-5890(81)90024-9. PMID 6977702.
- ^ a b Smith KA, Favata MF, Oroszlan S (October 1983). "Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics". J. Immunol. 131 (4): 1808–15. PMID 6352804.
- ^ Kasakura S, Lowenstein L (November 1965). "A factor stimulating DNA synthesis derived from the medium of leukocyte cultures". Nature 208 (5012): 794–5. doi:10.1038/208794a0. PMID 5868897.
- ^ Gordon J, MacLean LD (November 1965). "A lymphocyte-stimulating factor produced in vitro". Nature 208 (5012): 795–6. doi:10.1038/208795a0. PMID 4223737.
- ^ Gillis S, Smith KA (July 1977). "Long term culture of tumour-specific cytotoxic T cells". Nature 268 (5616): 154–6. doi:10.1038/268154a0. PMID 145543.
- ^ Baker PE, Gillis S, Smith KA (January 1979). "Monoclonal cytolytic T-cell lines". J. Exp. Med. 149 (1): 273–8. doi:10.1048/jem.149.273. PMC 2184737. PMID 310861.
- ^ Gillis S, Ferm MM, Ou W, Smith KA (June 1978). "T cell growth factor: parameters of production and a quantitative microassay for activity". J. Immunol. 120 (6): 2027–32. PMID 307029.
- ^ Robb RJ, Munck A, Smith KA (November 1981). "T cell growth factor receptors. Quantitation, specificity, and biological relevance". J. Exp. Med. 154 (5): 1455–74. doi:10.1084/jem.154.5.1455. PMC 2186509. PMID 6975347.
- ^ 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): 305–10. doi:10.1038/302305a0. PMID 6403867.
- ^ Kasakura S, Taguchi M, Watanabe Y, Okubo T, Murachi T, Uchino H, Hanaoka M (December 1984). "A mitogenic factor, released by stimulated human mononuclear cells and distinct from interleukin 2 (IL 2), B cell growth factor (BCGF), and interleukin 1 (IL 1)". J. Immunol. 133 (6): 3084–90. PMID 6238094.
- ^ Cantrell DA, Smith KA (June 1984). "The interleukin-2 T-cell system: a new cell growth model". Science 224 (4655): 1312–6. doi:10.1126/science.6427923. PMID 6427923.
- ^ Smith KA (May 1988). "Interleukin-2: inception, impact, and implications". Science 240 (4856): 1169–76. doi:10.1126/science.3131876. PMID 3131876.
- ^ Stern JB, Smith KA (July 1986). "Interleukin-2 induction of T-cell G1 progression and c-myb expression". Science 233 (4760): 203–6. doi:10.1126/science.3523754. PMID 3523754.
- ^ Beadling C, Johnson KW, Smith KA (April 1993). "Isolation of interleukin 2-induced immediate-early genes". Proc. Natl. Acad. Sci. U.S.A. 90 (7): 2719–23. doi:10.1073/pnas.90.7.2719. PMC 46167. PMID 7681987.
- ^ Beadling C, Smith KA (November 2002). "DNA array analysis of interleukin-2-regulated immediate/early genes". Med Immunol 1 (1): 2. doi:10.1186/1476-9433-1-2. PMC 149405. PMID 12459040.
- ^ Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (August 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 (3): 1151–64. PMID 7636184.
- ^ Thornton AM, Shevach EM (July 1998). "CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production". J. Exp. Med. 188 (2): 287–96. doi:10.1084/jem.188.2.287. PMC 2212461. PMID 9670041.
- ^ Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (June 2004). "Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function". J. Immunol. 172 (11): 6519–23. PMID 15153463.
- ^ Waldmann TA (August 2006). "The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design". Nat. Rev. Immunol. 6 (8): 595–601. doi:10.1038/nri1901. 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. doi:10.1146/annurev.immunol.17.1.19. PMID 10358752.
- ^ Recchia F, et al "Extended phase II study of maintenance immunotherapy in advanced cancer" AACR 2012; Abstract 5366 http://www.medpagetoday.com/MeetingCoverage/AACR/32048
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