IL-2 is a pleiotropic cytokine that plays an important role in the immune system, with "paradoxical" biological activity of immunostimulation or immunosuppression, and the effects on non-hematopoietic and innate immune cells are uncertain. However, IL-2 has been identified as a regulator of T cell development and homeostasis, and is a cytokine that induces CD8+ and CD4+ T cell proliferation. IL-2 also has other biological activities, such as increasing cytolytic activity, promoting antibody production, B cell proliferation, etc.
IL-2 is the first cytointerleukin factor to be cloned and the first factor approved for use in tumors**, and was named T cell growth factor (TCGF) in the early stage, which belongs to the cytokine family members.
IL-2 is mainly produced by CD4+ T cells. The regulation of IL2 gene expression involves a variety of transcription factors, including nuclear factor (NFAT), activator protein 1 (AP-1), nuclear factor B (NF-B), octamer-binding protein 1 (Pou2F1), high mobility group protein (HMGA1), and FOXP3 protein of activated T cell family members.
IL-2 activates three main signaling pathways: Jak-stat, ERK, and PI3K.
IL-2 receptor is a heteromeer composed of three chains, i.e., IL-2R is composed of IL-2R (CD25), IL-2R (CD122), and IL-2R (CD132). Among them, it is necessary for the activation of downstream signaling pathways, and it mainly promotes the combination of the two. When the IL-2 receptor subunit (IL-2RA) is present alone, its affinity for IL-2 is only one percent of that of the complete IL-2 receptor, so IL-2R is divided into high, medium, and low affinity receptors.
rosanne spolski et al. nat rev immunol
IL2RA is expressed in Treg cells. IL2RA transcription is enhanced after stimulation of T cells by TCR or IL-2. Other cytokines can also induce transcription, such as IL-7, IL-12, IL-15, TNF, and TGF-. IL2RB and IL2RG are expressed in a variety of cells, such as resting T cells, CD8+ T cells, natural killer cells, and certain other cell types. IL2RB transcription is controlled by a variety of transcription factors, including ETS1, GABP, SP1, EGR1, and EWS-WT1. There is limited information on IL2RG, and the IL2RG promoter contains multiple ETS binding sites that interact with GABP and ELF1 in vitro and thus may regulate promoter activity.
IL-2 was initially identified as a T cell growth factor, and as research progresses, more and more functions have been discovered, such as enhancing cytolytic activity, driving the development of Treg cells, inhibiting immune cell responses, and promoting potential cellular elimination through activation-induced cell death. In addition, IL-2 promotes the differentiation of various effector T cell populations. Therefore, the biological functions of IL-2 regulation or inhibition are diverse, with potential effects in a variety of diseases.
thomas a waldmann. cold spring harb perspect biol
From a clinical perspective, IL-2 is equally important. IL-2 can be used in patients with melanoma, renal cell carcinoma, and other types of tumors. IL-2 is a key growth factor for tumor-infiltrating lymphocytes, which can be expanded with IL-2 in vitro for sexual reinfusion to patients. The expansion of effector cells can be controlled by balancing the amount of IL-2 or by using new IL-2 analogues in combination with IL-2-specific antibodies.
In addition, IL-2 regulates the differentiation of CD4+ Th cell subsets. Th1 cells promote cellular immune responses against intracellular microbes and cancer cells. Th1 cell differentiation is mediated by IL-2, which coordinates the expression of the transcription factor TBX21. TH2 cells regulate humoral immunity to extracellular parasites and bacteria, as well as allergic inflammation. In the presence of IL-4, IL-2 promotes Th2 cell differentiation by upregulating IL-4 expression. Th17 cells coordinate adaptive defenses against extracellular pathogens, mediate inflammatory responses, and are involved in a variety of autoimmune diseases. IL-2 inhibits the differentiation of Th17 cells through multiple mechanisms, such as inhibition of IL-6RA and IL-17A. IL-2 also inhibits TFH cell differentiation that controls B cell response and germinal center formation. In primitive CD8+ T cells, IL-2 mediates the acquisition of an effector cytotoxic phenotype after antigen exposure by promoting the secretion of interferon-, interferon-, granzyme B, and perforin. The intensity of IL-2 IL-2R signaling activity transforms CD8+ T cells into short-lived effector cells or long-lived memory phenotypes.
IL-2R has been shown to be a receptor component not only of IL-2 but also of IL-4, IL-7, IL-9, IL-15, and IL-21, and is therefore now referred to as a common cytokine receptor chain (C).
IL-4 is a cytokine secreted by Th2, which has the function of stimulating the proliferation of activated B cells and T cells, and the differentiation of CD4+ T cells into Th2 cells, and plays an important role in regulating humoral immunity and adaptive immunity.
IL-7 has an effect on the survival, proliferation, and homeostasis of T cells through the C-receptor subunit. Elevated IL-7 expression leads to increased T cell proliferation and diversity. IL-7 also plays a role in B cell development.
IL-9 has a variety of functions and can induce the proliferation, differentiation and effector functions of a variety of immune cell subsets, and plays an important role in immune response and cancer pathogenesis. IL-9 is produced by a variety of cells, such as mast cells, NKT cells, TH2, TH17, TREG, ILC2, and TH9 cells.
IL-15, like IL-2, provides an early stimulus for T cell proliferation and activation, but IL-15 blocks IL-2-induced apoptosis. IL-15 supports the persistence of memory CD8+ T cells and is important for maintaining long-term anti-tumor immunity, and IL-15-related drugs have entered clinical studies in cancer and hematologic malignancies.
thomas a waldmann. cold spring harb perspect biol
IL-21 has close homology to IL2, IL4, and IL15, and is distinguished from other C cytokines by activating STAT1 and STAT3. IL-21 is predominantly produced by activated CD4+ T cells and has pleiotropic effects, including promoting CD4+ and CD8+ T cell proliferation and enhancing the cytotoxicity of CD8+ T cells and NK cells, but not activation-induced cell death.
Overall, IL-2 has a powerful effect on the immune system, and with the continuous understanding of the complex mechanism of action of IL-2 and receptor molecules on immune cells, it provides a blueprint for the development of more targeted cancer or autoimmune diseases, especially new ones for inflammatory autoimmune chronic diseases.
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