IL15RA - interleukin 15 receptor subunit alpha |Elisa - Clia - Antibody - Protein

Background

Interleukin-15 receptor subunit alpha (IL15RA) is a receptor that binds to the cytokine interleukin-15 (IL-15), a protein central to immune system regulation, particularly in the development, activation, and survival of natural killer (NK) cells and memory CD8+ T cells. IL-15 plays a significant role in the immune response against viral infections and tumors and in sustaining long-lived immune memory. Unlike many other cytokine receptors, IL15RA binds IL-15 with very high affinity even without the presence of other receptor subunits, making it essential for IL-15’s function. This interaction is critical in immune homeostasis and is relevant in inflammation, cancer immunology, and autoimmune disease contexts.

Protein Structure

The IL15RA protein has a distinct structural composition tailored to its high-affinity binding with IL-15:

Extracellular Domain:

• The extracellular portion of IL15RA contains several key regions essential for ligand binding, including sushi domains (also known as complement control protein domains or CCP domains). These domains form a binding interface that recognizes and binds IL-15 with picomolar affinity, even when IL15RA is expressed alone, without the need for other receptor subunits.
• IL15RA has multiple N-linked glycosylation sites within the extracellular domain, contributing to proper protein folding, stability, and binding efficacy with IL-15. Glycosylation is essential to maintain receptor conformation, which is necessary for high-affinity binding.

Transmembrane Domain:

• IL15RA has a single hydrophobic transmembrane helix that anchors the receptor into the plasma membrane. This transmembrane region ensures that the extracellular domain is optimally positioned on the cell surface for ligand binding.

Intracellular Domain:

• The cytoplasmic or intracellular tail of IL15RA is relatively short and lacks typical signaling motifs such as tyrosine kinase domains or phosphorylation sites. This is indicative of IL15RA’s role as a binding component rather than a direct signal transducer.
• Although IL15RA’s intracellular domain does not directly signal, it plays a structural role, enabling the receptor to participate in trans-presentation, a mechanism where IL-15 bound to IL15RA on one cell (e.g., dendritic cell) can stimulate IL-15Rβ/γ signaling on an adjacent immune cell (e.g., T or NK cell).

Classification and Subtypes

IL15RA belongs to the type I cytokine receptor family and is classified specifically as part of the IL-15 receptor complex, which also includes IL-2/15Rβ (CD122) and common gamma chain (γc, CD132). This trimeric complex is necessary for signal transduction of IL-15, although IL15RA alone can bind IL-15 with high affinity. While IL15RA itself does not have known subtypes, its expression varies across different cell types, including dendritic cells, monocytes, NK cells, and CD8+ T cells, with notable expression differences influencing the type of immune responses generated in various tissues.

Function and Biological Significance

IL15RA is critical for modulating IL-15’s role in immunity, which encompasses functions in immune cell development, activation, survival, and memory formation:

IL-15 Binding and Trans-Presentation:

• The unique function of IL15RA lies in its ability to “trans-present” IL-15. IL15RA binds IL-15 on the surface of cells like dendritic cells and monocytes and then presents this IL-15 to neighboring T or NK cells that express IL-2/15Rβ and γc. This “trans-presentation” mechanism ensures effective activation of IL-15-dependent cells without the need for these cells to synthesize IL-15 themselves.
• Trans-presentation by IL15RA is fundamental for the homeostasis and activation of NK cells and memory CD8+ T cells, particularly in maintaining these cells in a state of readiness for rapid immune response to infections or tumors.

Role in NK Cell and T Cell Development:

• IL15RA is indispensable in the development and proliferation of NK cells and memory CD8+ T cells. In the absence of IL15RA or IL-15, NK cell populations are markedly reduced due to impaired development. IL15RA-bound IL-15 signaling ensures that these cells survive and expand, enabling them to carry out cytotoxic functions against infected or transformed cells.
• Additionally, IL15RA’s regulation of IL-15 availability is crucial for the persistence of memory CD8+ T cells. These cells require intermittent IL-15 signaling to maintain a low level of activation, which allows them to respond swiftly upon re-exposure to previously encountered pathogens.

Role in Inflammatory and Autoimmune Diseases:

• IL15RA expression modulates IL-15’s effects in inflammatory and autoimmune diseases, where IL-15 is often elevated and contributes to excessive immune activation. In autoimmune diseases like rheumatoid arthritis, IL15RA-mediated IL-15 signaling supports T cell and macrophage activation, exacerbating inflammation and contributing to tissue damage.
• Modulation of IL15RA or IL-15 signaling is therefore a target in autoimmune conditions, aiming to reduce excessive immune responses that result from continuous IL-15 activity.

Role in Cancer:

• IL15RA plays an important role in cancer immunity due to IL-15’s ability to activate NK and CD8+ T cells, which can recognize and kill cancer cells. High levels of IL15RA expression and IL-15 trans-presentation on dendritic cells and other antigen-presenting cells can enhance anti-tumor immune responses.
• Some cancer therapies are exploring IL-15-based treatments to boost IL15RA-mediated trans-presentation, thereby enhancing NK cell and CD8+ T cell activity against tumors. Additionally, IL15RA's expression on certain cancer cells may modulate the tumor microenvironment, either promoting immune evasion or sensitizing the tumor to immune-mediated destruction.

Clinical Issues

IL15RA and IL-15 signaling have been implicated in various clinical conditions, ranging from immune deficiencies to inflammatory diseases and cancers:

Immune Deficiencies:

• IL15RA deficiency or mutations in IL15RA-related pathways can lead to immunodeficiency, particularly affecting NK cell development and function. Individuals with IL15RA deficiencies have reduced NK cell populations and may exhibit compromised immune responses to viral infections, highlighting the clinical importance of IL15RA in immune system competence.

Autoimmune Diseases:

• Overexpression of IL-15 and dysregulated IL15RA-mediated trans-presentation have been implicated in autoimmune diseases like rheumatoid arthritis, celiac disease, and inflammatory bowel disease. In these conditions, excessive IL-15 signaling driven by IL15RA promotes the survival and activation of autoreactive T cells and NK cells, contributing to chronic inflammation and tissue damage. Therapeutic interventions targeting IL15RA or IL-15 aim to reduce this pathological immune activation.

Cancer Immunotherapy:

• IL15RA’s role in facilitating IL-15 trans-presentation to NK and CD8+ T cells makes it a valuable target in cancer immunotherapy. IL-15-based therapies, including IL-15 superagonists and IL-15/IL15RA fusion proteins, are being developed to enhance anti-tumor immune responses. These therapies aim to potentiate NK cell and T cell responses within the tumor microenvironment, making IL15RA an indirect but pivotal participant in these emerging treatments.
• The targeted activation of IL-15 pathways via IL15RA is being investigated for treating solid tumors, hematologic malignancies, and improving the efficacy of other immunotherapeutic agents like CAR T cells and immune checkpoint inhibitors.

Transplantation:

• IL15RA is relevant in transplantation medicine, where IL-15 signaling can contribute to graft rejection by enhancing immune cell activation. Blocking IL-15 or IL15RA interactions has been studied as a means to induce tolerance in transplantation by preventing T cell and NK cell-mediated rejection.

Summary

IL15RA is a unique and indispensable component of the immune system’s response to IL-15, a cytokine crucial for the survival, development, and activation of NK cells and memory CD8+ T cells. Structurally, IL15RA is characterized by a highly specific cytokine-binding domain, a single transmembrane segment, and a short intracellular tail, which together facilitate its high-affinity binding with IL-15 and its role in trans-presenting IL-15 to other cells.

IL15RA’s ability to bind IL-15 independently and trans-present it to neighboring immune cells is critical for maintaining immune homeostasis, supporting immune memory, and enhancing rapid responses to pathogens or tumors. Its role in immune regulation makes it a key player in inflammatory diseases, autoimmune conditions, and cancer immunology, where it influences NK and T cell activity. Clinically, IL15RA is involved in immune deficiency syndromes, autoimmune diseases, and cancers, and it is a therapeutic target in each of these areas.

Emerging therapies targeting IL15RA or IL-15 pathways offer new avenues for treating autoimmune diseases, enhancing cancer immunity, and improving transplant outcomes, highlighting the receptor’s biological and therapeutic importance.