IL2RA - interleukin 2 receptor subunit alpha |Elisa - Clia - Antibody - Protein

Background

Interleukin 2 receptor subunit alpha (IL2RA), also known as CD25, is a crucial component of the high-affinity interleukin-2 (IL-2) receptor complex, which is essential for regulating immune responses, particularly T-cell proliferation and survival. The IL-2 receptor plays a pivotal role in both adaptive immunity and immune tolerance, with IL2RA being one of the three subunits that form the IL-2 receptor complex. The IL-2 receptor system is critically involved in the regulation of T-cell homeostasis, immune activation, and the suppression of autoimmunity.

IL2RA is primarily expressed on activated T cells, particularly regulatory T cells (Tregs), which are crucial for maintaining immune tolerance. It is also found on other immune cells, including activated B cells, dendritic cells, and natural killer (NK) cells under certain conditions. Importantly, IL2RA expression is tightly regulated, being upregulated upon T-cell activation and playing a central role in fine-tuning immune responses.

In the clinical context, IL2RA is associated with several diseases, particularly autoimmune disorders such as type 1 diabetes (T1D) and multiple sclerosis (MS), as well as in cancer immunology, where it can influence the tumor microenvironment. Furthermore, IL2RA is a target for immunotherapy, especially in the treatment of conditions like organ transplantation rejection, where modulation of IL-2 signaling can prevent graft-versus-host disease (GVHD).

Protein Structure

The IL2RA (CD25) protein is a transmembrane glycoprotein composed of 272 amino acids. It is one of three subunits that make up the interleukin-2 receptor (IL-2R) complex. The IL-2R complex has three subunits: IL-2RA (CD25), IL-2RB (CD122), and the common gamma chain (γc, CD132). Of these, IL2RA is unique in that it does not directly signal itself but is essential for creating the high-affinity IL-2 receptor when combined with the other two subunits.

Key structural features of IL2RA include:

Extracellular Domain:

• The extracellular domain of IL2RA is responsible for binding interleukin-2 (IL-2). This region is characterized by two fibronectin type III domains, which are essential for IL-2 binding. Although IL2RA binds IL-2 with low affinity on its own, when it combines with the IL-2RB and γc subunits, the overall receptor complex can bind IL-2 with high affinity, allowing effective signal transduction.
• The N-terminal region of IL2RA is also glycosylated, with N-linked glycans contributing to the protein’s stability and function. These glycosylation sites help protect the protein from proteolytic degradation and enhance its ability to interact with IL-2.

Transmembrane Domain:

• IL2RA has a single-pass transmembrane domain that anchors it to the plasma membrane of immune cells. This region spans the lipid bilayer, playing a role in stabilizing the receptor at the cell surface, and is important for localization in membrane microdomains involved in receptor clustering.

Cytoplasmic Tail:

• The cytoplasmic domain of IL2RA is short and lacks intrinsic signaling capacity. Unlike the other two subunits (IL-2RB and γc), which have longer cytoplasmic tails that are involved in signal transduction through pathways like JAK-STAT (Janus kinase-signal transducer and activator of transcription), IL2RA does not participate directly in intracellular signaling. Its primary function is to enhance the receptor’s affinity for IL-2 by promoting complex formation with IL-2RB and γc.

Classification and Subtypes

IL2RA (CD25) is classified as a type I transmembrane protein within the cytokine receptor family. IL2RA is not divided into subtypes per se, but it exists in two primary forms:

Membrane-bound IL2RA:

• This form is expressed on the surface of activated T cells, Tregs, and other immune cells. It is the form that participates in the formation of the high-affinity IL-2 receptor complex with IL-2RB and γc.

Soluble IL2RA (sIL2RA):

• IL2RA can also be shed from the cell surface through proteolytic cleavage, resulting in a soluble form of the receptor (sIL2RA). This soluble form can still bind IL-2 but does not signal. Elevated levels of sIL2RA in the serum are associated with immune activation and are used as biomarkers for autoimmune diseases and cancer.

Function and Biological Significance

IL2RA has several key roles, primarily related to immune regulation and signaling in the IL-2 receptor complex:

Regulation of T-cell Proliferation:

• IL-2 is a potent cytokine that drives T-cell proliferation and survival. IL2RA, in conjunction with IL-2RB and γc, forms the high-affinity IL-2 receptor, which is essential for the proliferation of effector T cells following activation. The ability of IL-2 to drive clonal expansion of T cells makes it crucial for the adaptive immune response.

Role in Regulatory T Cells (Tregs):

• Tregs are critical for maintaining immune tolerance and preventing autoimmune diseases. These cells express high levels of CD25, allowing them to effectively compete for IL-2. IL2RA expression on Tregs is crucial for their development, survival, and function. By consuming IL-2, Tregs can limit the availability of this cytokine for effector T cells, thereby preventing excessive immune activation.

Immune Tolerance and Autoimmunity:

• The IL2RA subunit is essential for immune tolerance, especially through its role in Treg function. Defects in CD25 expression or IL-2 signaling can lead to autoimmune diseases, such as type 1 diabetes, multiple sclerosis, and autoimmune polyendocrine syndromes. IL2RA helps maintain immune homeostasis, preventing the immune system from attacking self-tissues.

Role in Immune Suppression and Cancer:

• IL2RA is frequently overexpressed on activated T cells in the tumor microenvironment, as well as on some types of cancer cells, including leukemia and lymphomas. High CD25 expression helps these cells evade immune destruction by creating an environment where Tregs dominate, suppressing anti-tumor immune responses. This makes IL2RA a potential target for cancer immunotherapies, aiming to disrupt the immunosuppressive networks within tumors.

Clinical Issues

Autoimmune Diseases:

• Mutations or polymorphisms in the IL2RA gene are associated with several autoimmune conditions. Reduced or impaired IL2RA function can compromise Treg development and lead to the breakdown of immune tolerance, contributing to the onset of diseases such as:
• Type 1 diabetes (T1D): IL2RA polymorphisms have been linked to an increased risk of T1D, where the immune system attacks insulin-producing β-cells in the pancreas.
• Multiple sclerosis (MS): Defective IL2RA function has been associated with MS, an autoimmune disorder where the immune system targets the myelin sheath in the central nervous system.
• Autoimmune polyendocrine syndrome: Deficiencies in IL-2 signaling, due to CD25 mutations, can result in a range of autoimmune disorders affecting multiple endocrine organs.

Cancer:

• High CD25 expression is often seen in cancers such as leukemias and lymphomas, particularly in adult T-cell leukemia (ATL) and Hodgkin’s lymphoma. The overexpression of CD25 allows cancer cells to exploit IL-2 signaling for survival and proliferation. Additionally, tumor-infiltrating regulatory T cells (Tregs) that express high levels of CD25 can suppress anti-tumor immune responses, allowing cancer cells to evade immune surveillance.
• Therapeutic approaches targeting CD25 include monoclonal antibodies such as daclizumab and basiliximab, which are designed to block IL2RA and inhibit the IL-2 signaling pathway, thus preventing the growth of certain cancers or controlling excessive immune activation.

Organ Transplantation:

• IL2RA is targeted in transplantation medicine to prevent graft rejection. In organ transplant recipients, drugs such as basiliximab (anti-CD25 monoclonal antibody) are used to block IL-2 signaling, thereby reducing the proliferation of T cells that could lead to rejection of the transplanted organ. This approach has proven effective in reducing the incidence of acute rejection episodes in kidney transplantation.

Immunodeficiency Disorders:

• Mutations in the IL2RA gene can result in immunodeficiency syndromes. For example, IL2RA deficiency leads to severe combined immunodeficiency (SCID), characterized by a lack of functional T cells and a severely compromised immune system.

Summary

IL2RA (CD25) is an essential component of the interleukin-2 receptor complex, playing a crucial role in T-cell proliferation, immune regulation, and autoimmune tolerance. It is primarily expressed on activated T cells, regulatory T cells (Tregs), and other immune cells, facilitating the formation of the high-affinity IL-2 receptor required for IL-2 signaling. IL2RA has significant biological importance, particularly in controlling immune homeostasis and preventing excessive immune responses that can lead to autoimmunity. Clinically, IL2RA is involved in autoimmune diseases, cancer, immunodeficiencies, and organ transplantation. It is a therapeutic target for immunosuppressive drugs used in transplantation and autoimmunity, as well as for cancer therapies aimed at modulating immune responses.