IL21R- interleukin 21 receptor |Elisa - Clia - Antibody - Protein

Background

Interleukin 21 receptor (IL21R) is a member of the cytokine receptor superfamily, specifically involved in immune cell communication and regulation. IL21R binds interleukin-21 (IL-21), a cytokine that plays crucial roles in immune response modulation, primarily impacting the activity of T cells, B cells, and natural killer (NK) cells. IL-21/IL21R signaling is essential for adaptive immunity, supporting the differentiation, proliferation, and functional enhancement of immune cells. This receptor is expressed on a wide range of cells within the immune system, including T and B lymphocytes, NK cells, dendritic cells, and some epithelial cells. Given its immunoregulatory functions, IL21R signaling has implications in autoimmunity, cancer immunology, and chronic inflammatory conditions.

Protein Structure

The IL21R protein structure includes several distinct regions that facilitate cytokine binding, signal transduction, and interaction with other receptor components. IL21R is a type I transmembrane glycoprotein composed of approximately 538 amino acids and features the following structural domains:

Extracellular Domain:

• The extracellular region of IL21R is composed of around 200 amino acids and contains two primary subdomains: a fibronectin type III domain and a cytokine-binding module (CBM). The cytokine-binding module is a characteristic motif found in cytokine receptors, facilitating specific ligand binding. The binding of IL-21 to IL21R involves this CBM and a fibronectin III domain, where it forms a stable cytokine-receptor complex.
• IL21R forms a heterodimer with the common gamma chain (γc), also known as IL2RG, which is shared by multiple cytokine receptors such as those for IL-2, IL-4, and IL-7. This heterodimerization is necessary for IL-21 binding, and the interaction with the γc component enhances receptor stability and signal transduction capability.

Transmembrane Domain:

• A single transmembrane helix anchors IL21R to the cell membrane. This transmembrane region is essential for maintaining IL21R orientation on the cell surface and enables interactions between IL21R and the common gamma chain receptor, which is also membrane-bound. This association allows efficient recruitment and activation of downstream signaling molecules.

Intracellular Domain:

• The intracellular region of IL21R, which comprises approximately 130 amino acids, contains several tyrosine residues that become phosphorylated following IL-21 binding and receptor activation. These phosphorylation sites provide docking points for downstream signaling molecules, such as Janus kinases (JAK1 and JAK3) and signal transducers and activators of transcription (STAT3 and STAT5).
• Upon ligand binding, JAKs associated with IL21R’s intracellular domain phosphorylate STATs, which subsequently dimerize and translocate to the nucleus to influence the expression of genes related to immune function, cell proliferation, and apoptosis.

Classification and Subtypes

IL21R is classified as part of the type I cytokine receptor family, which shares a conserved extracellular cytokine-binding motif. Within this family, IL21R is grouped with other receptors that utilize the common gamma chain (IL2RG) for signaling, forming a unique subgroup of receptors known as the common gamma chain receptor family. Members of this subgroup are particularly important for lymphocyte development and immune system regulation. Unlike other cytokine receptors, IL21R does not have distinct isoforms or subtypes, though splice variants have been observed in some studies. These variants may influence receptor expression and signaling efficiency in specific immune contexts.

Function and Biological Significance

IL21R is primarily involved in immune regulation through its interaction with IL-21, which drives various functions in lymphocytes and innate immune cells:

T Cell Regulation:

• IL21R is expressed on CD4+ and CD8+ T cells, where IL-21 signaling enhances T cell survival, expansion, and cytokine production. In particular, IL21R engagement is crucial for the differentiation and maintenance of T follicular helper (Tfh) cells, a subset of CD4+ T cells that support B cell function and antibody production.
• IL-21/IL21R signaling also augments the cytotoxic activity of CD8+ T cells, enhancing their ability to kill infected or cancerous cells. This makes IL21R signaling a significant contributor to cellular immune responses, particularly in infections and tumor surveillance.

B Cell Development and Antibody Production:

• In B cells, IL21R signaling supports the differentiation of naive B cells into plasma cells and promotes class-switch recombination, a critical process for antibody diversity. By influencing B cell maturation, IL21R contributes to robust humoral immunity.
• IL21R signaling in B cells also promotes immunoglobulin production, including IgG, IgA, and IgE. This receptor’s role in antibody production underscores its relevance in vaccine responses and protective immunity against pathogens.

Natural Killer (NK) Cell Function:

• IL21R is expressed on NK cells, where IL-21 binding enhances their cytotoxicity and production of interferon-gamma (IFN-γ). The enhancement of NK cell function through IL21R is critical for innate immunity, allowing NK cells to efficiently target and eliminate virally infected cells and tumors.

Modulation of Inflammatory Responses:

• Beyond lymphocyte activation, IL21R signaling influences dendritic cells and macrophages, modulating inflammatory responses. IL-21 enhances cytokine production in these cells, amplifying the immune response during infection or injury.
• However, IL21R signaling must be tightly regulated, as excessive activation can contribute to chronic inflammation and autoimmune conditions. The receptor’s role in modulating inflammation is evident in autoimmune pathologies where IL21R is overexpressed or dysregulated.

Clinical Issues

Autoimmune Diseases:

• Dysregulated IL21R signaling is implicated in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D). IL-21 is often elevated in these conditions, contributing to excessive B cell activation, antibody production, and autoreactive T cell survival.
• In RA, for example, IL21R signaling exacerbates joint inflammation and tissue damage by promoting the survival of autoreactive immune cells. Targeting IL21R or its signaling pathway is an area of interest in developing therapies for autoimmune diseases.

Immunodeficiencies:

• Mutations or deficiencies in IL21R have been linked to certain immunodeficiency disorders characterized by compromised T and B cell responses. Patients with IL21R deficiencies may present with recurrent infections due to impaired antibody production and inadequate T cell responses.

Cancer:

• IL21R expression and IL-21 signaling have shown dual roles in cancer. On one hand, IL21R signaling in immune cells, especially T and NK cells, supports anti-tumor immunity by enhancing their cytotoxic function. Thus, IL21R is being explored as a target in cancer immunotherapy.
• Conversely, in some cancers, IL21R signaling in the tumor microenvironment can support tumor cell survival and immune evasion. IL-21/IL21R axis modulation may benefit specific cancer therapies by selectively enhancing anti-tumor immunity.

Chronic Inflammatory Disorders:

• Chronic conditions such as inflammatory bowel disease (IBD) have been associated with dysregulated IL21R signaling. Elevated IL-21 levels in the gastrointestinal tract contribute to persistent inflammation, supporting IL21R as a potential therapeutic target in inflammatory diseases.

Summary

The interleukin-21 receptor (IL21R) is a critical component of the cytokine receptor family, primarily mediating immune functions through its interaction with IL-21. Structurally, IL21R consists of an extracellular domain that binds IL-21, a transmembrane region, and an intracellular signaling domain with sites for tyrosine phosphorylation. This receptor is part of the common gamma chain family and forms a complex with the IL2RG chain, essential for cytokine binding and signal transduction.

Functionally, IL21R influences immune responses across multiple cell types. It regulates T and B cell differentiation, enhances NK cell cytotoxicity, and modulates inflammation through interactions with dendritic cells and macrophages. These functions position IL21R as a key player in adaptive and innate immunity, supporting both protective and regulatory immune functions.

Clinically, IL21R dysregulation is implicated in autoimmune diseases, immunodeficiencies, cancers, and chronic inflammatory conditions. In autoimmune diseases, excessive IL21R signaling drives autoreactive immune cell survival and inflammation. In cancers, IL21R enhances T and NK cell responses against tumor cells, while in other cases, it may promote tumor growth and immune evasion. Due to its role in immune regulation, IL21R is a therapeutic target for treating autoimmune disorders, cancers, and chronic inflammatory diseases.