IL2RG - interleukin 2 receptor subunit gamma | Elisa - Clia - Antibody - Protein

Background

The Interleukin 2 Receptor Subunit Gamma (IL2RG), also known as the common gamma chain or γc, is a crucial component of several cytokine receptor complexes, specifically those for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Each of these cytokines plays a vital role in immune cell development, activation, and homeostasis. Because IL2RG is part of multiple cytokine receptor systems, it is often referred to as a "common" subunit, essential for the signaling functionality of these cytokines. The expression of IL2RG is indispensable for immune competence, influencing processes in adaptive immunity and innate immune responses. In its absence, severe immunodeficiency conditions, such as X-linked severe combined immunodeficiency (X-SCID), can occur, indicating its role in T cell, B cell, and natural killer (NK) cell development.

IL2RG does not directly bind to cytokines but facilitates signal transduction by forming a complex with cytokine-specific receptor subunits and initiating intracellular signaling cascades. The signaling through IL2RG activates critical pathways, including JAK/STAT, MAPK, and PI3K/AKT, which are integral to immune cell differentiation, proliferation, and survival. Due to the centrality of IL2RG in immune system function, mutations in this gene have severe implications for immune cell functionality and host defense.

Protein Structure

The IL2RG protein is a type I transmembrane glycoprotein composed of 369 amino acids, with a molecular weight of approximately 43 kDa. It is organized into three distinct regions: the extracellular domain, transmembrane domain, and intracellular domain, each playing a specific role in IL2RG’s function.

Extracellular Domain (ECD):

• The ECD of IL2RG spans approximately 227 amino acids and contains two fibronectin type III (FNIII) domains. These domains are crucial for the interaction with other cytokine receptor subunits, specifically binding to the alpha or beta chains of the receptor complexes.
• There are also N-linked glycosylation sites within this domain, which stabilize the structure, facilitate receptor expression on the cell surface, and assist in proper protein folding. These glycosylation sites contribute to IL2RG’s structural stability and functionality within cytokine receptor complexes.
• A crucial WSXWS motif is also present in the ECD. This highly conserved sequence is typical of cytokine receptors and is essential for proper receptor folding and cell surface localization, allowing IL2RG to interact efficiently with other receptor subunits.

Transmembrane Domain (TMD):

• The TMD is a hydrophobic region that anchors IL2RG within the cellular membrane, providing stability and maintaining its orientation relative to other receptor components. This structural feature is fundamental for the receptor's proper alignment, although it does not play a direct role in signaling.

Intracellular Domain (ICD):

• The ICD is essential for intracellular signaling and contains specific tyrosine residues that become phosphorylated upon receptor activation. This phosphorylation recruits Janus kinases (JAKs), particularly JAK3, which is necessary for transmitting signals downstream via the JAK/STAT signaling pathway.
• The ICD also interacts with other signaling proteins involved in the MAPK/ERK and PI3K/AKT pathways, which regulate cell survival, proliferation, and differentiation. Notably, JAK3’s recruitment to IL2RG is required to initiate STAT phosphorylation and signal propagation within immune cells, making the ICD critical for cytokine-driven immune responses.

Classification and Subtypes

IL2RG is classified within the type I cytokine receptor family and is part of the hematopoietin receptor superfamily. It functions as the common gamma chain (γc) and is shared across multiple cytokine receptor systems, specifically those for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Although there are no subtypes of IL2RG, its functionality differs based on the cytokine receptor complex in which it participates, enabling a broad range of immune-modulating activities.

Function and Biological Significance

The IL2RG protein is crucial for transmitting cytokine signals that regulate various aspects of the immune system:

Role in T and B Lymphocyte Development and Function:

• IL2RG is essential for T cell development, survival, and activation. Through IL-2 signaling, it supports T cell proliferation and differentiation, directly impacting adaptive immunity.
• In B cells, IL2RG's role in IL-4 signaling is crucial for class-switching and antibody production, which are vital for effective immune responses against pathogens.

Natural Killer (NK) Cell Development:

• IL2RG, especially in the IL-15 receptor complex, is indispensable for NK cell differentiation and function. NK cells are part of the innate immune system and play a role in controlling viral infections and tumor cells. Without functional IL2RG, NK cell populations are drastically reduced or dysfunctional.

Regulation of Immune Homeostasis:

• Through IL-7 signaling, IL2RG helps maintain lymphocyte homeostasis and survival, particularly in T cells during their early developmental stages. IL2RG-mediated signaling pathways ensure that the immune system can mount adequate responses and maintain immune cell populations.

Broad Immune Modulation:

• IL2RG also contributes to inflammation regulation through IL-9 and IL-21 signaling, affecting various cell types, including mast cells, eosinophils, and certain T cell subsets.
• Given that IL2RG is shared by cytokines with various immunomodulatory effects, it plays a broad role in immune regulation, enhancing both immune activation and regulation as needed.

Clinical Issues

Mutations in the IL2RG gene are linked to significant clinical conditions due to the role IL2RG plays in immune function:

X-linked Severe Combined Immunodeficiency (X-SCID):

• Mutations in the IL2RG gene cause X-SCID, a severe immunodeficiency characterized by a near-complete absence of functional T cells and NK cells, as well as non-functional B cells. Patients with X-SCID are highly susceptible to infections and require early treatment, often involving bone marrow transplantation or gene therapy.
• X-SCID is lethal if untreated, but advancements in gene therapy targeting IL2RG have shown promise, providing a long-term cure for this immunodeficiency by introducing functional IL2RG genes into patient cells.

Leukemia and Other Hematological Malignancies:

• IL2RG signaling pathways, when overactivated or dysregulated, have been implicated in certain cancers, particularly those involving lymphoid cells. Excessive or inappropriate IL-2 or IL-4 signaling through IL2RG can contribute to aberrant cell proliferation and survival, potentially leading to malignancies.
• Targeting IL2RG or downstream pathways (e.g., JAK inhibitors) in such malignancies is under exploration, especially for leukemias driven by cytokine signaling dysregulation.

Autoimmune and Inflammatory Disorders:

• Dysregulated IL2RG function, particularly in IL-4 and IL-21 signaling, is linked to autoimmune diseases such as lupus and rheumatoid arthritis. Overactivation of these pathways can lead to abnormal immune responses, causing tissue inflammation and damage.
• Therapeutic interventions targeting IL2RG signaling pathways may provide treatment options for inflammatory conditions by modulating cytokine activity and reducing inflammatory responses.

Gene Therapy Applications:

• IL2RG gene therapy has demonstrated success in correcting immune deficiencies in X-SCID patients, with early clinical trials showing restored immune function in treated individuals. The therapeutic approach involves using viral vectors to deliver functional IL2RG genes into patient hematopoietic stem cells, providing a long-term, functional immune system.

Summary

IL2RG, as the common gamma chain, is an indispensable component of several cytokine receptor complexes essential for immune cell development, proliferation, and function. Its structure includes an extracellular domain with fibronectin type III domains, a transmembrane domain, and an intracellular domain with phosphorylation sites for signal transduction. Through its role in cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, IL2RG facilitates JAK/STAT, MAPK, and PI3K/AKT signaling pathways, affecting a wide range of immune functions.

Clinically, IL2RG mutations lead to X-SCID, a life-threatening immunodeficiency that requires early intervention. Aberrations in IL2RG function also contribute to autoimmune diseases and certain cancers. Gene therapy advancements targeting IL2RG show promise in treating X-SCID and potentially other immune-related disorders. Overall, IL2RG is critical for the functional immune system, and understanding its mechanisms provides insight into immune dysregulation and therapeutic potential in immunodeficiency and autoimmune conditions.