Common Gamma-Chain Family
Available Resources for the Study of Common Gamma-Chain Family
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- Moreover, we provide comprehensive resources, such as involved pathways, protein function, interacting proteins, and other valuable information to support research endeavors and enhance their impact.
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About Common Gamma-Chain Family
The common gamma chain (γc) family refers to a group of cytokines and their corresponding receptors that share a common receptor subunit called the γc or interleukin-2 receptor gamma chain (IL-2Rγ or CD132). This family of cytokines plays essential roles in immune system regulation, cell development, and various physiological processes. The receptors of the γc family, along with their associated cytokines, activate specific signaling pathways that play crucial roles in immune cell function and development. Here are some of the signaling pathways and downstream effects associated with these receptors:
IL-2 signaling pathway
- IL-2 binds to the IL-2 receptor (IL-2R), which consists of IL-2Rα (CD25), IL-2Rβ (CD122), and the common gamma chain (γc).
- The binding of IL-2 to the IL-2R triggers the activation of Janus kinases (JAKs) and subsequent phosphorylation of the receptor subunits.
- This leads to the recruitment and activation of signaling molecules such as signal transducer and activator of transcription 5 (STAT5), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs).
- Activation of these signaling pathways promotes T cell proliferation, survival, and immune regulation.
- IL-2 signaling also contributes to the development and maintenance of regulatory T cells (Tregs), which play a critical role in immune tolerance and suppression of excessive immune responses.
IL-4 signaling pathway
- IL-4 binds to the IL-4 receptor (IL-4R), which consists of IL-4Rα (CD124) and the common gamma chain (γc).
- The binding of IL-4 to the IL-4R triggers the activation of JAKs and subsequent phosphorylation of the receptor subunits.
- This leads to the activation of STAT6 and the PI3K-Akt pathway.
- Activation of these pathways promotes the differentiation of CD4+ T cells into Th2 cells, which are involved in allergic and humoral immune responses.
- IL-4 signaling also stimulates B cell growth, antibody production, and class switching to IgE.
IL-7 signaling pathway
- IL-7 binds to the IL-7 receptor (IL-7R), which consists of IL-7Rα (CD127) and the common gamma chain (γc).
- The binding of IL-7 to the IL-7R activates JAKs and subsequent phosphorylation of the receptor subunits.
- This leads to the activation of STAT5 and the PI3K-Akt pathway.
- IL-7 signaling is critical for T cell development, survival, and homeostasis.
- It promotes the survival and proliferation of immature T cells in the thymus and supports the maintenance of memory T cells in the periphery.
IL-9 signaling pathway
- IL-9 binds to the IL-9 receptor (IL-9R), which consists of IL-9Rα and the common gamma chain (γc).
- The binding of IL-9 to the IL-9R activates JAKs and subsequent phosphorylation of the receptor subunits.
- This leads to the activation of STAT proteins and the PI3K-Akt pathway.
- IL-9 signaling promotes mast cell proliferation and activation, contributing to allergic responses.
- It also influences the differentiation of helper T cell subsets, including Th9 cells.
IL-15 signaling pathway
- IL-15 binds to the IL-15 receptor (IL-15R), which consists of IL-15Rα, IL-2Rβ, and the common gamma chain (γc).
- The binding of IL-15 to the IL-15R triggers JAK activation and subsequent phosphorylation of the receptor subunits.
- This leads to the activation of STAT proteins and the PI3K-Akt pathway.
- IL-15 signaling is crucial for the development, survival, and activation of natural killer (NK) cells and memory CD8+ T cells.
- It supports the maintenance of these cell populations and enhances their anti-tumor and anti-viral activities.
IL-21 signaling pathway
- IL-21 binds to the IL-21 receptor (IL-21R), which consists of IL-21R and the common gamma chain (γc).
- The binding of IL-21 to the IL-21R activates JAKs and subsequent phosphorylation of the receptor subunits.
- This leads to the activation of STAT proteins, particularly STAT3, and the MAPK pathway.
- IL-21 signaling regulates B cell activation, antibody production, and immune responses.
- It influences the formation of germinal centers and the differentiation of B cells into plasma cells and memory B cells.
In summary, the γc family encompasses a group of cytokines that utilize the common gamma chain as a receptor subunit. These cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, have diverse functions in immune regulation and cell development. Their receptor complexes, which include specific receptor subunits along with the common gamma chain, mediate their signaling and regulate various physiological processes in the immune system.
Fig.1 Schematic of γ chain (γc) family cytokines and their receptors. (Lin JX, et al., 2018)
Shown are how Janus kinase (JAK)1 and JAK3 associate with each receptor, the signal transducers and activators of transcription (STAT) proteins activated by each cytokine, and the major actions of these cytokines on the development and function immune cells. The STAT proteins predominantly activated by each cytokine are in bold.
Therapeutic Strategies Targeting the γc Receptors for the Treatment of Various Diseases
Therapeutic strategies targeting the receptors in the common γc family have shown promise in the treatment of various diseases. Here are some examples of therapeutic approaches that focus on these receptors:
Monoclonal Antibodies
Monoclonal antibodies (mAbs) can be designed to target the receptors of the common γc family, either blocking their function or enhancing their activity. Some examples include:
- Anti-IL-2R antibodies: Monoclonal antibodies targeting IL-2 receptor subunits, such as IL-2Rα (CD25) and IL-2Rβ (CD122), have been developed. These antibodies can block IL-2 binding and inhibit IL-2 signaling, which can be beneficial in conditions where excessive immune responses need to be suppressed, such as autoimmune diseases.
- Anti-IL-4R antibodies: Monoclonal antibodies against IL-4 receptor subunits, such as IL-4Rα (CD124), can disrupt IL-4 signaling. By blocking IL-4-induced Th2 cell differentiation and B cell activation, these antibodies have potential applications in allergic diseases and asthma.
- Anti-IL-7R antibodies: Monoclonal antibodies targeting IL-7 receptor subunits, including IL-7Rα (CD127), have been developed. These antibodies can interfere with IL-7 signaling, which may be beneficial in conditions where T-cell proliferation and survival need to be controlled, such as certain types of leukemia.
Small Molecule Inhibitors
In addition to monoclonal antibodies, small molecule inhibitors can be used to target the signaling pathways associated with the receptors of the common γc family. Some examples include:
- JAK inhibitors: Janus kinases (JAKs) are key components in the signaling pathways activated by these receptors. Small molecule inhibitors targeting JAKs can block downstream signaling events. JAK inhibitors have shown efficacy in various immune-related diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
- PI3K inhibitors: The PI3K-Akt pathway is another important signaling pathway downstream of these receptors. Small molecule inhibitors of PI3K can interfere with this pathway, potentially modulating immune cell function. PI3K inhibitors are being investigated in clinical trials for various cancers and autoimmune diseases.
These are just a few examples of therapeutic strategies targeting the receptors in the common γc family. It's worth mentioning that the development and clinical use of these therapies are ongoing, and their efficacy and safety continue to be evaluated through preclinical and clinical studies. The specific choice of therapeutic approach depends on the disease, the specific receptor targeted, and the desired outcome, and it is determined on a case-by-case basis.
Fig.2 Schematic of the γc family of cytokines. (Leonard W J, et al., 2019)
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Related References
- Leonard W J, Lin J X, O'Shea J J. The γc family of cytokines: basic biology to therapeutic ramifications[J]. Immunity, 2019, 50(4): 832-850.
- Lin JX, Leonard WJ. The Common Cytokine Receptor γ Chain Family of Cytokines. Cold Spring Harb Perspect Biol. 2018;10(9):a028449. Published 2018 Sep 4.
