IL2RB - interleukin 2 receptor subunit beta | Elisa - Clia - Antibody - Protein

Background

IL2RB, or interleukin-2 receptor beta subunit, is a crucial component of the interleukin-2 (IL-2) receptor complex. The IL-2 receptor is vital for T cell activation, proliferation, and survival and is central to immune responses. IL2RB, specifically, is essential for transmitting signals that control the growth, differentiation, and survival of T cells. The IL-2 receptor complex consists of three subunits: the IL-2 receptor alpha (IL2RA or CD25), IL-2 receptor beta (IL2RB or CD122), and IL-2 receptor gamma (IL2RG or CD132). Together, these subunits form a high-affinity receptor for IL-2 that is primarily expressed on activated T cells, natural killer (NK) cells, and other immune cell types.

IL2RB, encoded by the IL2RB gene on chromosome 22q12.3, is a key signaling subunit. It binds IL-2 with intermediate affinity independently but, when combined with IL2RG, forms the high-affinity IL-2 receptor that effectively transmits intracellular signals upon IL-2 binding. IL2RB plays a significant role in immune homeostasis and regulation, influencing T cell differentiation, NK cell development, and peripheral tolerance. Dysregulation of IL2RB expression or function is linked to various immune disorders, including autoimmune diseases, immunodeficiencies, and certain cancers.

Protein Structure

IL2RB has a unique structure optimized for binding IL-2 and interacting with signaling molecules:

Extracellular Domain (ECD):

• The extracellular region of IL2RB is composed of 214 amino acids and includes two fibronectin type III-like domains, which are essential for IL-2 binding. These domains provide structural stability and interact directly with the IL-2 ligand.
• The ECD is highly specific and, together with IL2RA and IL2RG, allows the receptor to form a high-affinity binding site for IL-2. In the absence of IL2RA, the IL2RB and IL2RG subunits together can bind IL-2 with intermediate affinity.
• IL2RB is glycosylated within the ECD, with N-linked glycosylation contributing to protein stability and possibly affecting ligand binding.

Transmembrane Domain (TMD):

• The TMD of IL2RB anchors the protein in the cell membrane. It is composed of a single alpha-helical transmembrane region, allowing IL2RB to position the extracellular domain properly for ligand binding and signal initiation.

Intracellular Domain (ICD):

• The intracellular domain is integral to the signaling function of IL2RB. The ICD lacks intrinsic kinase activity but interacts with several cytoplasmic kinases and adaptor proteins, primarily Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 5 (STAT5).
• Phosphorylation of tyrosine residues within the ICD initiates downstream signaling cascades, most notably the JAK-STAT pathway, which leads to gene transcription involved in cell proliferation, differentiation, and survival.
• IL2RB also has binding motifs that allow interaction with other signaling molecules such as LCK and PI3K, contributing to the activation of additional signaling pathways, including the MAPK/ERK pathway.

Classification and Subtypes

IL2RB is classified as part of the cytokine receptor family, specifically within the Type I cytokine receptor family. Cytokine receptors in this family typically bind signaling molecules that regulate immune responses, inflammation, and hematopoiesis.

While IL2RB itself does not have subtypes, it is part of several receptor complexes in the cytokine receptor family. The IL-2 receptor complex, for example, can exist in different affinity states depending on which subunits are present:

• High-affinity IL-2 receptor: Formed by IL2RA, IL2RB, and IL2RG.
• Intermediate-affinity IL-2 receptor: Formed by IL2RB and IL2RG alone.

Function and Biological Significance

The IL-2 receptor complex, with IL2RB as a central component, has several significant functions in immune regulation:

T Cell Proliferation and Activation:

• IL-2 is a key growth factor for T cells, and IL2RB plays a crucial role in transmitting the signals required for T cell proliferation. Activation of the JAK-STAT pathway upon IL-2 binding leads to the transcription of genes that promote T cell growth and cell cycle progression.
• IL2RB is also essential for the survival of memory T cells, helping maintain long-term immunity after an infection or immunization.

Differentiation of Regulatory T Cells (Tregs):

• IL2RB is vital for the development and function of regulatory T cells (Tregs), which help maintain immune tolerance and prevent autoimmune reactions. IL-2 signaling through IL2RB supports the expression of FOXP3, a transcription factor that defines Tregs, and enables their suppressive function on effector T cells.

Natural Killer (NK) Cell Development:

• IL2RB is expressed on NK cells, where it mediates IL-2-driven maturation and activation. NK cells are part of the innate immune system and are critical for responding to infected or malignant cells. Through IL2RB signaling, IL-2 enhances NK cell cytotoxicity and proliferation, improving immune defense mechanisms.

Control of Immune Homeostasis and Tolerance:

• IL2RB signaling is fundamental in establishing immune tolerance by supporting Tregs and preventing excessive T cell activation. Balanced IL-2 signaling, mediated by IL2RB, is essential for avoiding autoimmune responses and maintaining immune homeostasis.
• IL-2 receptor signaling, particularly through IL2RB, supports a feedback mechanism to maintain peripheral tolerance, preventing the immune system from attacking self-antigens.

Role in Anti-Tumor Immunity:

• IL2RB-mediated signaling also contributes to anti-tumor immunity, as IL-2 promotes the activation and proliferation of cytotoxic T cells and NK cells, both of which are critical for recognizing and eliminating cancer cells.

Clinical Issues

The role of IL2RB in immune function implicates it in several clinical conditions:

Autoimmune Diseases:

• Defects or mutations in IL2RB can lead to autoimmune diseases such as type 1 diabetes and rheumatoid arthritis. Reduced IL2RB function affects Treg survival and function, leading to a failure in immune tolerance mechanisms and allowing self-reactive T cells to proliferate unchecked.
• Therapeutic interventions aimed at enhancing IL-2 signaling through IL2RB, such as low-dose IL-2 therapy, are being explored for their potential to increase Treg function and reduce autoimmunity.

Immunodeficiencies:

• Severe combined immunodeficiency (SCID) is a condition associated with defects in the common gamma chain (IL2RG), which forms part of the IL-2 receptor with IL2RB. This genetic disorder leads to an absence of functional T cells and NK cells, resulting in severe vulnerability to infections.
• Mutations directly in IL2RB are rare but can result in impaired immune responses and predispose individuals to infections due to compromised T and NK cell function.

Cancer:

• IL2RB is also relevant in cancer immunotherapy. IL-2 has been used clinically to boost anti-tumor immune responses, especially for cancers such as melanoma and renal cell carcinoma. However, high-dose IL-2 can cause severe side effects due to overstimulation of immune cells.
• Research into selectively targeting IL2RB on Tregs within the tumor microenvironment could improve anti-tumor responses while avoiding systemic immune activation.

Therapeutic Targeting in Transplantation:

• IL2RB is a potential target for immunosuppressive therapies in transplant medicine. Modulating IL-2 signaling to reduce effector T cell activity and promote Treg expansion could help prevent graft rejection while minimizing the need for broad immunosuppression.

Summary

IL2RB, or interleukin-2 receptor subunit beta, is a vital component of the IL-2 receptor complex involved in immune cell proliferation, differentiation, and survival. Structurally, IL2RB consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain that transmits signals essential for T cell and NK cell responses. IL2RB, along with IL2RG, binds IL-2 and activates pathways necessary for immune regulation, primarily through the JAK-STAT pathway.

IL2RB’s biological functions are essential for T cell and NK cell activity, Treg function, and immune homeostasis. Clinically, IL2RB dysregulation or mutations can lead to autoimmune diseases, immunodeficiencies, and potential cancer proliferation. Targeted therapies leveraging IL2RB’s role in immune regulation, including low-dose IL-2 therapy and specific cancer immunotherapies, are under exploration to harness its benefits while mitigating potential side effects. The IL2RB receptor remains a significant focus in immunology research for its extensive involvement in immune homeostasis and potential therapeutic applications.