Common Cytokine Receptor Gamma Chain Family Cytokines

Common Cytokine Receptor Gamma Chain Family Cytokines, Receptors and Signaling Pathways

IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines known as the common cytokine receptor gamma chain family. Cytokines belonging to this family signal through receptor complexes that contain a shared subunit, known as the common cytokine receptor gamma chain subunit. This subunit associates with either IL-4 R alpha, IL-7 R alpha, IL-9R, or IL-21R to form heterodimeric receptors for IL-4, IL-7, IL-9, or IL-21 respectively, or it associates with both IL-2 R alpha and IL-2/IL-15 R beta or IL-15 R alpha and IL-2/IL-15 R beta to form heterotrimeric receptor complexes for IL-2 or IL-15. In addition to sharing a common receptor subunit, members of the common cytokine receptor gamma chain family are all class I short chain four alpha-helix bundle cytokines with similar structural features. Following receptor binding, they activate similar intracellular signaling pathways, including Jak-STAT signaling, PI 3-K-Akt signaling, and Ras-MAPK signaling, leading to the expression of specific target genes.

Common Cytokine Gamma Chain Family Cytokines Regulate Immune Cell Development and Functions

Functionally, cytokines belonging to the common cytokine receptor gamma chain family are involved in regulating the development, survival, proliferation, differentiation and functions of different immune cell types. As a result, they affect the activities of multiple cell types, including natural killer cells, innate lymphoid cells, T cells, and B cells. Cytokines in this family can also have both unique and overlapping effects. Their unique functions are primarily determined by differences in their expression patterns or the expression of their unique receptor subunits, or by activation of different STAT proteins. The importance of common cytokine receptor gamma chain signaling for immune system development and maintenance is emphasized by the fact that mutations in the human common gamma chain/IL-2 R gamma are associated with X-linked severe combined immunodeficiency (XSCID). XSCID is a life-threatening disease in which patients lack T cells and natural killer cells and have nonfunctional B cells that produce significantly reduced levels of immunoglobulin. Importantly, it was discovered that IL-2 knockout mice and patients deficient in IL-2 do not mimic the XSCID phenotype, leading to the realization that the common cytokine receptor gamma chain must serve as a receptor component for other cytokines as well.

IL-2

IL-2 is produced primarily by CD4⁺ T cells, although it can also be produced at lower levels by CD8⁺ T cells, dendritic cells, natural killer cells, NKT cells, and B cells. It signals through a receptor complex consisting of IL-2 R alpha/CD25, IL-2 R beta, and the common gamma chain/IL-2 R gamma subunit. IL-2 plays a central role in stimulating CD4⁺ and CD8⁺ T cell proliferation, and it regulates peripheral self-tolerance by promoting activation-induced cell death (AICD) in CD4⁺ T cells. IL-2 promotes Th1, Th2, and Th9 cell differentiation, while inhibiting the differentiation of Th17 and T follicular helper (Tfh) cells. Additionally, IL-2 stimulates the proliferation and cytotoxicity of natural killer cells, enhances B cell functions, and promotes the development and maintenance of regulatory T cells (Tregs). IL-2 has been approved as an anti-cancer treatment for melanoma and renal cancer, and it is being evaluated as a potential treatment for autoimmune diseases due to its ability to promote regulatory T cell homeostasis.

IL-4

IL-4 is produced primarily by T cells, NKT cells, mast cells, and eosinophils. It signals through two different receptor complexes, a type I receptor complex consisting of IL-4 R alpha and the common gamma chain/IL-2 R gamma subunit, and a type II receptor complex consisting of IL-4 R alpha and IL-13 R alpha 1. The type I receptor complex is expressed on hematopoietic cells and is specific for IL-4, while the type II receptor complex is expressed on nonhematopoietic cells and some hematopoietic cells and can be activated by either IL-4 or IL-13. IL-4 is a signature cytokine for Th2-type immune responses and is essential for providing protection against large extracellular parasites. It also promotes B cell differentiation and immunoglobulin class switching, Th2 and Th9 cell differentiation, M2 macrophage activation, and mast cell survival and proliferation. Due to its central role in regulating Th2-type immune responses, IL-4 is thought to play a central role in mediating the development of allergic inflammation and asthma.

IL-7

IL-7 is produced primarily by stromal cells, epithelial cells, and keratinocytes, and it signals through a receptor complex consisting of IL-7 R alpha and the common gamma chain/IL-2 R gamma subunit. IL-7 signaling is required for T cell development and homeostasis in both mice and humans, mouse B cell development, and the generation and survival of CD4⁺ and CD8⁺ memory T cells. The requirement of IL-7 for the maintenance of T cell survival has in part been attributed to its ability to induce the expression of the anti-apoptotic proteins, Bcl-2, Bcl-xL, and Mcl-1. Additionally, IL-7 is required for maintaining the homeostasis of thymic natural killer cells and is involved in regulating V(D)J recombination at the TCR and distal Ig heavy chain loci.

IL-9

IL-9 is produced primarily by Th9 cells, mast cells, ILC2 cells, and NKT cells, and it signals through a receptor complex consisting of IL-9 R alpha and the common gamma chain/IL-2 R gamma subunit. IL-9 was originally thought to be produced by Th2 cells, but it was later discovered to be the signature cytokine of Th9 cells. IL-9 promotes mast cell proliferation, enhances IL-4-induced IgG and IgE production by B cells, and promotes goblet cell hyperplasia and mucus production. It is thought to contribute to the development of allergic inflammation and asthma, but it as also been shown to have anti-cancer activity.

IL-15

IL-15 is produced primarily by dendritic cells, monocytes, macrophages, epithelial cells, fibroblasts, and stromal cells. It binds with high affinity to IL-15 R alpha, which then associates with IL-2/IL-15 R beta and the common gamma chain/IL-2 R gamma, either in cis (on the same cell) or in trans (on a different cell). IL-15 signaling is required for the development and maintenance of natural killer cells and memory CD8⁺ T cells. Similar to IL-2, IL-15 can stimulate the cytotoxicity of CD8⁺ T cells and natural killer cells, but in contrast to IL-2, it inhibits activation-induced cell death. Additionally, IL-15 promotes the expansion and homeostasis of NKT cells and intestinal intraepithelial lymphocytes. IL-15 is considered to be a promising anti-cancer agent, particularly when used in combination with other anti-cancer agents such as immune checkpoint inhibitors or agonistic anti-CD40 antibodies.

IL-21

IL-21 is produced primarily by Th17 cells, T follicular helper (Tfh) cells, NKT cells, and gamma delta T cells. It binds to a receptor complex consisting of IL-21 R and the common gamma chain/IL-2 R gamma subunit. IL-21 signaling promotes Th17 and T follicular helper cell differentiation, while inhibiting the differentiation of Th9 cells and regulatory T cells (Tregs). Additionally, IL-21 enhances the cytotoxicity of CD8⁺ cells, natural killer cells, and NKT cells, regulates B cell proliferation and apoptosis in a context-dependent manner, and promotes B cell differentiation and immunoglobulin production, in the presence of IL-4. IL-21 has been shown to have anti-tumor activity, but it is also associated with the pathogenesis of autoimmune disease in mouse models of type I diabetes, systemic lupus erythematosus (SLE), and experimental autoimmune uveitis.  

Bio-Techne offers a wide selection of proteins, antibodies, and immunoassays for cytokines belonging to the common cytokine receptor gamma chain family. Our catalog includes research-grade, Animal-Free^TM, and GMP-grade bioactive IL-2, IL-4, IL-7, IL-15, and IL-21. Additionally, we offer antibodies validated for blocking/neutralization, flow cytometry, ICC, or Western blot, and immunoassays for measuring these cytokines in various sample types.