IL12RB1 - interleukin 12 receptor subunit beta 1 |Elisa - Clia - Antibody - Protein

Background

Interleukin 12 receptor subunit beta 1 (IL12RB1) is a protein that serves as an integral component of the interleukin-12 receptor (IL-12R) complex, a receptor system critical for immune function. IL12RB1 is encoded by the IL12RB1 gene and is highly expressed in immune cells, primarily on T cells, natural killer (NK) cells, and macrophages. It plays a central role in mediating immune responses, specifically by binding to the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), which are essential for driving Th1-type immune responses and promoting cell-mediated immunity. Through this role, IL12RB1 is key in defending the body against intracellular pathogens such as Mycobacterium tuberculosis and certain viruses.

The IL-12R complex comprises two main subunits: IL12RB1 and IL12RB2. IL12RB1 forms a binding receptor for both IL-12 and IL-23, and its expression level and function are vital for proper immune function. Genetic mutations in IL12RB1 are linked to immunodeficiency syndromes, as individuals with these mutations have impaired responses to IL-12 and IL-23, resulting in compromised resistance to infections. The receptor’s functionality is therefore critical for immune cell activation, proliferation, and differentiation, particularly within the adaptive immune response.

Protein Structure

IL12RB1 is a type I transmembrane glycoprotein with a distinct structural organization that supports its role in cytokine binding and signal transduction. The protein structure includes:

Extracellular Domain:

• The extracellular region of IL12RB1 consists of a large cytokine receptor homology domain (CRH), containing two fibronectin type III (FNIII) domains. These FNIII domains are important for the structural integrity of the receptor and for binding interactions with IL-12 and IL-23.
• Ligand-Binding Sites: Specific regions within the extracellular domain facilitate binding to the p40 subunit of IL-12 and IL-23, which enables the formation of the signaling complex necessary for activating downstream immune responses. The extracellular domain has both high-affinity and low-affinity binding sites that influence how effectively the receptor can bind and respond to different cytokines.
• N-Linked Glycosylation: The extracellular domain contains several glycosylation sites, which contribute to the stability and functionality of the receptor. Glycosylation helps to maintain receptor conformation and may impact binding affinity and surface expression.

Transmembrane Domain:

• The single transmembrane domain of IL12RB1 anchors the receptor to the plasma membrane, positioning the extracellular domain to interact with IL-12 and IL-23 in the extracellular space. This domain also interacts with the transmembrane region of IL12RB2, forming a stable receptor complex on the cell surface.

Intracellular (Cytoplasmic) Domain:

• The intracellular domain contains motifs for downstream signaling. While IL12RB1 itself does not possess intrinsic kinase activity, it interacts with Janus kinase 2 (JAK2), which is essential for initiating the JAK-STAT signaling cascade upon ligand binding. This association with JAK2 is crucial for transmitting signals through the STAT4 pathway, leading to gene transcription necessary for Th1 differentiation and IFN-γ production.
• The cytoplasmic domain of IL12RB1 also has tyrosine residues that can undergo phosphorylation, further aiding in signal transduction upon cytokine binding.

The structure of IL12RB1, including its extracellular ligand-binding domains and its interactions with JAK2, supports its specialized role in cytokine recognition and immune activation. The receptor forms a heterodimer with IL12RB2 to initiate the signaling cascade required for immune response modulation.

Classification and Subtypes

IL12RB1 belongs to the type I cytokine receptor family, specifically the Class I cytokine receptor family (also known as the hematopoietic cytokine receptor family). This family is characterized by the presence of conserved extracellular fibronectin type III domains and their involvement in immune cell signaling.

IL12RB1 does not have subtypes but does work in tandem with other interleukin receptor subunits:

• IL12RB2: Co-receptor specifically for IL-12. The binding of IL-12 to IL12RB1 recruits IL12RB2 to form the functional IL-12 receptor complex, enabling downstream signaling through the JAK-STAT pathway.
• IL23R: Co-receptor specifically for IL-23. IL12RB1 also pairs with IL23R to form the IL-23 receptor, triggering distinct but overlapping immune responses that promote Th17 differentiation.

Function and Biological Significance

IL12RB1 has a key role in immune defense, particularly in orchestrating responses against intracellular pathogens. It achieves this by working as a part of two major cytokine receptor complexes:

1. IL-12 Receptor Complex: When IL-12 binds to IL12RB1, it recruits IL12RB2, forming a receptor complex that activates JAK2 and TYK2 kinases. This interaction initiates the phosphorylation of STAT4, a transcription factor essential for Th1 differentiation and IFN-γ production. IFN-γ is critical for macrophage activation and pathogen destruction, particularly in bacterial and viral infections. Therefore, the IL-12/IL-12R pathway is central to protective immunity and the clearance of intracellular pathogens.
2. IL-23 Receptor Complex: IL12RB1 also binds IL-23 in cooperation with IL23R. This complex, through JAK2-STAT3 signaling, promotes the differentiation and expansion of Th17 cells, which are involved in the immune response against extracellular bacteria and fungi. Th17 cells produce cytokines like IL-17, which are critical for mucosal defense and inflammatory responses, and are particularly important in barrier immunity.

The dual role of IL12RB1 in forming both IL-12 and IL-23 receptors enables it to orchestrate the balance between Th1 and Th17 responses. This balance is critical for immune homeostasis, ensuring effective pathogen clearance while minimizing potential for inflammatory or autoimmune damage.

Clinical Issues

Given IL12RB1’s critical role in immune function, deficiencies or mutations in the IL12RB1 gene can lead to significant clinical conditions:

1. Primary Immunodeficiency Disorders: Mutations in IL12RB1 are associated with IL-12 receptor β1 deficiency, an autosomal recessive immunodeficiency. This condition impairs the body's ability to respond to IL-12 and IL-23, leading to a reduced Th1 response and increased susceptibility to infections, especially mycobacterial and salmonella infections. Patients with IL12RB1 deficiency may exhibit recurrent infections and have difficulty clearing pathogens, especially mycobacteria, even in non-tuberculous forms. This immunodeficiency highlights the receptor’s essential role in pathogen clearance.
2. Autoimmune and Inflammatory Diseases: Dysregulation in IL12RB1 expression or function can contribute to autoimmune conditions. Since IL-12 and IL-23 pathways are central to both Th1 and Th17 responses, aberrant signaling through these pathways may lead to chronic inflammation and autoimmunity. Overactive Th1 responses are associated with conditions like Crohn's disease and multiple sclerosis, while Th17 dominance is implicated in psoriasis and rheumatoid arthritis. Therapeutics that target IL-12 and IL-23 signaling pathways are thus employed to treat these autoimmune disorders by reducing inflammation.
3. Cancer: The IL-12/IL12RB1 axis is also relevant in cancer immunology. IL-12 has anti-tumor properties through its role in enhancing cytotoxic T cell and NK cell activity. Therapies that boost IL-12 signaling, or recombinant IL-12 treatments, have been explored to enhance anti-tumor immunity, though their application is complicated by potential toxicity. Understanding IL12RB1’s role in immune modulation may help develop safer and more targeted cancer immunotherapies.
4. Vaccine Responses: The efficacy of some vaccines may be impacted by IL12RB1 function, as the receptor’s role in Th1 and Th17 responses is crucial for mounting a strong immune defense. Individuals with IL12RB1 deficiency may have a diminished response to vaccines that rely on Th1-type immunity, such as the Bacillus Calmette-Guérin (BCG) vaccine for tuberculosis.

Summary

IL12RB1, a type I transmembrane receptor, is a critical component of the IL-12 and IL-23 receptor complexes. Its structure includes extracellular cytokine-binding domains, a transmembrane region, and a cytoplasmic domain that interacts with JAK2 kinase to initiate downstream signaling. This receptor is essential for immune cell differentiation, particularly of Th1 and Th17 cells, which are pivotal in the response to intracellular pathogens and the modulation of inflammatory responses.

Clinically, IL12RB1 is associated with primary immunodeficiencies, where mutations lead to increased susceptibility to infections like tuberculosis and salmonellosis. Additionally, its role in Th1 and Th17 signaling implicates it in autoimmune diseases, such as Crohn’s disease and psoriasis, as well as cancer immunology. Therapies that target the IL-12 and IL-23 pathways are employed in treating autoimmune and inflammatory conditions, with potential applications in cancer treatment as well.

In summary, IL12RB1’s functionality in IL-12 and IL-23 signaling underpins critical immune responses. By mediating Th1 and Th17 pathways, IL12RB1 balances immune activation and regulatory mechanisms, influencing responses to pathogens and impacting a variety of immunological and clinical conditions.