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IL2

Official Full Name
interleukin 2
Organism
Homo sapiens
GeneID
3558
Background
This gene is a member of the interleukin 2 (IL2) cytokine subfamily which includes IL4, IL7, IL9, IL15, IL21, erythropoietin, and thrombopoietin. The protein encoded by this gene is a secreted cytokine produced by activated CD4+ and CD8+ T lymphocytes, that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine (IL2R) is a heterotrimeric protein complex whose gamma chain is also shared by IL4 and IL7. The expression of this gene in mature thymocytes is monoallelic, which represents an unusual regulatory mode for controlling the precise expression of a single gene. The targeted disruption of a similar gene in mice leads to ulcerative colitis-like disease, which suggests an essential role of this gene in the immune response to antigenic stimuli. [provided by RefSeq, Sep 2020]
Synonyms
IL-2; TCGF; lymphokine;
Bio Chemical Class
Cytokine: interleukin
Protein Sequence
MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
Open
Disease
Acute diabete complication, Adrenal cancer, Bipolar disorder, Brain cancer, Immune system disease, Lung cancer, Lupus erythematosus, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature T-cell lymphoma, Melanoma, Multiple sclerosis, Mycosis fungoides, Ovarian cancer, Prostate cancer, Renal cell carcinoma, Rheumatoid arthritis, Solid tumour/cancer
Approved Drug
2 +
Clinical Trial Drug
17 +
Discontinued Drug
6 +

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Detailed Information

Interleukin 2 (IL-2) is a critical cytokine in the immune system, produced by activated T cells, particularly CD4+ helper T cells. Its primary role is to promote the proliferation and differentiation of T and B lymphocytes, crucial for adaptive immune responses. IL-2 is also a growth factor for natural killer (NK) cells, further enhancing its importance in immune defense. This article will explore the essential functions of IL-2 in immune regulation, its therapeutic applications, and its role in immune-related diseases.

IL-2 and Its Receptor Structure

IL-2 belongs to a subfamily of cytokines that includes IL-4, IL-7, IL-9, IL-15, IL-21, erythropoietin, and thrombopoietin. As a secreted protein, IL-2 plays a pivotal role in modulating the immune system, with its secretion predominantly occurring from activated CD4+ T cells, and to a lesser extent, from CD8+ T cells and NK cells.

The IL-2 receptor (IL-2R) is a heterotrimeric protein complex, which consists of three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (CD132). These subunits come together to form a receptor complex that can exist in different configurations based on affinity for IL-2. The receptor's affinity for IL-2 is highest when all three subunits are present, forming a high-affinity receptor. A dimeric configuration of IL-2Rβ and IL-2Rγ forms a medium-affinity receptor, while IL-2Rα alone constitutes the lowest-affinity receptor. This variation in receptor affinity helps regulate the immune response by controlling the intensity of IL-2 signaling.

Figure 1 illustrates the interaction of IL-2 with its receptor subunits (IL-2Ralpha, IL-2Rbeta, and the common gamma-chain).Figure 1. IL-2 Receptor (IL-2R) Binding and Signaling. (Arenas-Ramirez N, et al., 2015)

Activation and Signaling Pathways

IL-2 binds to its receptor, initiating a cascade of intracellular signaling events that are essential for T cell proliferation, differentiation, and survival. Upon IL-2 binding, the receptor undergoes oligomerization, causing conformational changes in the IL-2R subunits. This activation leads to the phosphorylation of Janus kinases JAK1 and JAK3, which subsequently phosphorylate the receptor itself. This forms docking sites for downstream signaling molecules, including Signal Transducer and Activator of Transcription 5 (STAT5).

The activation of STAT5 is crucial for several cellular processes, including cell growth and differentiation. In addition to the STAT pathway, IL-2 receptor activation also triggers the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, both of which contribute to T cell expansion and function. These signaling pathways are essential for IL-2's role in the immune response, as they support the proliferation of T cells, the differentiation of T helper subsets (Th1, Th2, Th17), and the development of memory CD8+ T cells.

IL-2 in Immune Response and Disease

IL-2 has a wide range of functions in immune regulation. One of its most important roles is as a growth factor for T cells, promoting their proliferation and survival. It also supports B cell activation, enhancing antibody production as part of the humoral immune response. By modulating T regulatory cells (Tregs), IL-2 is crucial for maintaining immune tolerance and preventing autoimmune reactions. Tregs suppress excessive immune responses, ensuring that the immune system does not attack the body's own tissues.

Beyond its roles in normal immune function, IL-2 has significant implications in various diseases. It is involved in both the promotion and suppression of immune responses, depending on the context. In cancer immunotherapy, for example, recombinant IL-2 has been used to enhance the activity of cytotoxic T lymphocytes (CTLs) and NK cells, increasing their ability to target and destroy tumor cells. IL-2-based therapies have shown promise in treating cancers such as melanoma and renal cell carcinoma, though they can also lead to severe side effects like cytokine release syndrome.

IL-2 in Autoimmunity and Cancer Therapy

While IL-2 plays a protective role in the immune system, dysregulation of its signaling can contribute to autoimmune diseases. In conditions like rheumatoid arthritis and systemic lupus erythematosus (SLE), excessive IL-2 production and T cell activation can lead to the destruction of healthy tissues. To counter this, IL-2 receptor antagonists, such as basiliximab, are used to block IL-2 signaling, preventing the activation of T cells and offering therapeutic benefits in autoimmune diseases.

In contrast, IL-2's role in cancer immunotherapy has been a focus of extensive research. By boosting T cell and NK cell function, IL-2 can enhance the immune system's ability to recognize and attack tumor cells. However, its clinical application is complicated by potential side effects, such as fever, chills, and more severe complications like capillary leak syndrome. Despite these challenges, IL-2 therapy remains a key area of investigation in cancer treatment.

IL-2 in Allergic Responses

IL-2 is also involved in allergic diseases. It can influence the balance between different T helper cell subsets, particularly Th1 and Th2 cells. Th2 cells are involved in the production of cytokines like IL-4 and IL-13, which are central to allergic inflammation. IL-2 helps promote Th2 cell activation, which in turn drives allergic responses such as those seen in asthma and allergic rhinitis. Modulating IL-2 signaling pathways may provide new strategies for treating allergic diseases by reducing Th2-driven inflammation.

The mTOR Pathway and Immunosuppressive Therapies

IL-2 signaling activates multiple downstream pathways, one of the most significant being the mechanistic target of rapamycin (mTOR) pathway. mTOR is a critical regulator of cell growth, metabolism, and survival. By activating mTOR, IL-2 promotes T cell proliferation, but inhibiting mTOR has become a therapeutic strategy for controlling immune responses. Rapamycin, a potent mTOR inhibitor, can suppress T cell proliferation, making it a valuable tool for inducing immune tolerance in transplantation and autoimmune disease therapies.

The potential to manipulate IL-2 and its signaling pathways opens up many possibilities for therapeutic interventions. For example, IL-2 receptor antagonists can be used to suppress immune activation in autoimmune diseases, while IL-2-based therapies can boost immune responses against cancer. Furthermore, targeting the mTOR pathway provides an additional layer of control over T cell proliferation, which may be useful in managing both immune-related disorders and transplant rejection.

References:

  1. Abbas AK, Trotta E, R Simeonov D, et al. Revisiting IL-2: Biology and therapeutic prospects. Sci Immunol. 2018;3(25):eaat1482.
  2. Arenas-Ramirez N, Woytschak J, Boyman O. Interleukin-2: Biology, Design and Application. Trends Immunol. 2015;36(12):763-777.
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