IL9R - interleukin 9 receptor| Elisa - Clia - Antibody - Protein

Background

The interleukin-9 receptor (IL9R) is a key component of the immune system, primarily involved in mediating the biological activities of interleukin-9 (IL-9), a cytokine secreted by T helper 2 (Th2) cells, mast cells, and a subset of T helper cells known as Th9 cells. IL-9 is known for its pleiotropic effects, influencing various cell types including mast cells, T cells, B cells, and epithelial cells. It is particularly important in immune responses, inflammatory processes, and allergic reactions. IL9R, through binding IL-9, initiates signaling cascades that play critical roles in the regulation of cell survival, proliferation, and differentiation in immune responses.

The IL9R gene is located on the X chromosome (Xq28) in humans, which makes certain IL9R-related mutations have potential X-linked patterns of inheritance. Notably, IL9R signaling is involved in allergic diseases, asthma, and certain cancers. Additionally, IL-9 and IL9R have been implicated in autoimmune diseases and responses to infections, such as helminth infections. Due to its versatile role in immunity, IL9R is an area of interest for therapeutic strategies aiming to modulate immune responses, particularly in allergy and asthma, and cancer treatment.

Protein Structure

IL9R is a type I transmembrane receptor comprising approximately 520 amino acids. It functions as a part of a heterodimeric receptor complex, requiring the common gamma chain (γc), which is shared with other cytokine receptors, to mediate signal transduction.

Extracellular Domain (ECD):

• The ECD of IL9R contains about 200 amino acids and includes a cytokine receptor homology region that is critical for ligand binding. The structure includes two conserved fibronectin type III-like domains that facilitate cytokine interaction and receptor dimerization, which are necessary for the binding and recognition of IL-9.
• Conserved cysteine residues and a hallmark WSXWS motif within the ECD are essential for correct folding and structural stability of IL9R. Additionally, there are glycosylation sites that contribute to protein stability and protection from proteolytic degradation, enhancing the receptor’s functional integrity and longevity on the cell surface.

Transmembrane Domain (TMD):

• The TMD is a single alpha-helical region anchoring IL9R to the cell membrane. This domain is essential for positioning the receptor within the cell membrane, allowing it to interact efficiently with the γc and enable intracellular signaling cascades.

Intracellular Domain (ICD):

• The ICD contains approximately 150 amino acids and is responsible for the initiation of downstream signaling. The region lacks intrinsic kinase activity, so it relies on the recruitment of Janus kinase 1 (JAK1) and the activation of STAT proteins (primarily STAT1, STAT3, and STAT5) to transmit signals to the nucleus. Tyrosine residues within the ICD are phosphorylated upon receptor activation, providing docking sites for downstream signaling proteins.

Classification and Subtypes

IL9R is a member of the type I cytokine receptor family and is classified as part of the hematopoietin receptor superfamily, distinguished by its conserved structural features such as the WSXWS motif and the fibronectin type III domains. It is structurally similar to other receptors that utilize the γc for signal transduction, such as the IL-2, IL-4, and IL-15 receptors. While IL9R itself does not have subtypes, its function and signaling are heavily influenced by its interaction with the γc, a subunit that serves as a shared component for multiple cytokine receptors.

Function and Biological Significance

IL9R plays a vital role in the immune system, where IL-9/IL9R signaling affects various cell types and functions. Major functions and biological roles include:

Immune Cell Regulation:

• IL9R signaling regulates the development, differentiation, and survival of T cells and mast cells. It also influences the Th9 cell subset, promoting cytokine production that enhances immune responses against parasites and contributes to allergy-related inflammation.
• In mast cells and basophils, IL-9 signaling through IL9R promotes cell proliferation, survival, and the release of mediators involved in allergic reactions, such as histamines, further linking IL9R to allergic diseases.

Regulation of Mucosal Immunity:

• IL9R signaling has been shown to support mucosal immunity, particularly in the gut and respiratory tract, by enhancing mucus production and stimulating the activity of goblet cells. This response is beneficial for defense against parasitic infections, such as helminths, and plays a role in the pathophysiology of asthma by increasing mucus secretion and airway hyperreactivity.

Involvement in Inflammatory Responses:

• IL-9/IL9R signaling promotes the differentiation and survival of Th9 cells, which produce cytokines associated with inflammation and allergic responses. IL9R also mediates responses in epithelial cells, contributing to inflammation in tissues exposed to allergens, such as the lungs in asthma patients.

Influence on Tumor Immunity and Cancer:

• IL-9 has both pro- and anti-tumor effects depending on the type of cancer. In some cancers, IL-9 promotes tumor progression, while in others, IL-9/IL9R signaling can enhance anti-tumor immunity. IL9R is thus considered a potential target in cancer immunotherapy, with research exploring the modulation of IL-9/IL9R pathways to either inhibit tumor growth or enhance immune responses against cancer cells.

Clinical Issues

Dysregulation of IL9R or altered IL-9 signaling can contribute to various clinical conditions:

Asthma and Allergies:

• IL9R is implicated in asthma and atopic conditions. IL-9 signaling through IL9R contributes to airway hyperreactivity, mucus production, and eosinophilic inflammation. Elevated IL9R expression on immune cells in individuals with asthma and allergies suggests a role in disease pathogenesis, making IL9R a target for novel anti-inflammatory treatments.

Autoimmune Diseases:

• Increased IL9R signaling is associated with certain autoimmune diseases, such as systemic lupus erythematosus and inflammatory bowel disease (IBD). In these diseases, IL9R activation on T cells and other immune cells leads to enhanced immune responses, which can contribute to autoimmunity and inflammation in affected tissues.

Cancer:

• The role of IL9R in cancer is complex and context-dependent. In hematologic malignancies, such as Hodgkin lymphoma, IL-9 signaling may support cancer cell survival, whereas in some solid tumors, IL9R-mediated responses could stimulate immune cells to attack the tumor. Understanding the dual role of IL9R in cancer is a focus of ongoing research, and modulating IL-9/IL9R signaling is being explored in immunotherapeutic approaches.

Parasitic Infections:

• IL9R signaling plays a protective role in immunity against helminths and other parasites, with IL-9 promoting the activation of mast cells and mucus production that facilitate parasite expulsion. IL9R deficiency or mutations may impair responses to parasitic infections, leading to increased susceptibility.

Summary

IL9R is an essential component of the immune system, mediating the effects of IL-9 and influencing a range of immune functions. Structurally, it is a type I transmembrane protein with a ligand-binding extracellular domain, a single-pass transmembrane domain, and a cytoplasmic tail involved in signal transduction. Its association with the common gamma chain (γc) allows it to initiate downstream signaling cascades that regulate cell proliferation, survival, and differentiation, particularly in T cells, mast cells, and epithelial cells.

IL9R’s functions are diverse, affecting allergic inflammation, immunity against parasitic infections, and potentially modulating cancer immunity. Dysregulation or mutations in IL9R have clinical implications in asthma, autoimmune diseases, cancer, and immune responses to infections. As a result, IL9R is a target of interest in therapeutic strategies aimed at modulating immune responses, with particular promise in treating asthma, allergies, and potentially cancers where IL-9 signaling is a factor.

Research into IL9R continues to expand our understanding of its role in both normal immune function and disease. This receptor remains an important focus in immunology, and ongoing studies are expected to reveal further insights into its role in health and disease, as well as provide a basis for developing targeted therapies that harness or inhibit IL-9 signaling for therapeutic benefit.