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IL2RA
interleukin 2 receptor subunit alpha
IL2RA is located on the short (p) arm of chromosome 10, at band 10p15.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The IL2RA gene, located on chromosome 10, encodes the alpha subunit of the interleukin-2 receptor (IL-2R), also known as CD25. This protein forms part of a trimeric receptor complex that binds interleukin-2, a crucial signalling molecule in the immune system. The alpha chain substantially increases the receptor's affinity for IL-2, enabling efficient signal transduction in immune cells.
CD25 expression is particularly important on regulatory T cells (Tregs), where it facilitates immune tolerance and prevents autoimmune responses. Common genetic variants in IL2RA have been identified in genome-wide association studies of multiple autoimmune conditions, suggesting that subtle changes in receptor expression or function may influence disease susceptibility. The gene's role in immune regulation has made it a target of therapeutic intervention in transplantation and autoimmune disease.
What the gene does
The IL2RA protein functions as the alpha chain of the heterotrimeric interleukin-2 receptor, partnering with beta and gamma chains to create a high-affinity binding site for IL-2. When IL-2 binds to the complete receptor complex, it triggers intracellular signalling cascades that promote T-cell proliferation, survival, and functional differentiation. The alpha chain itself does not transmit signals but dramatically increases binding affinity from micromolar to picomolar range.
CD25 plays a particularly critical role in regulatory T cells, where constitutive expression enables these cells to respond to low concentrations of IL-2 in the tissue microenvironment. This sensitivity is essential for Treg development, maintenance, and suppressive function. The protein is also upregulated on activated conventional T cells, where it supports clonal expansion during immune responses. IL-2 signalling through this receptor complex influences the balance between immune activation and tolerance, affecting outcomes in infection, autoimmunity, and cancer immunosurveillance.
The receptor's expression is tightly regulated at the transcriptional level, with enhancer regions responding to immune signals and transcription factors. Alterations in this regulatory landscape can shift immune cell populations and modify disease risk.
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Chromosome location
IL2RA is located on the short arm of chromosome 10 at position 15.1 (10p15.1). The gene spans approximately 70 kilobases of genomic DNA and contains eight exons. This chromosomal region has been identified in linkage and association studies of autoimmune phenotypes, with several common variants in non-coding regulatory regions showing association with disease susceptibility.
Protein structure
The IL2RA protein comprises 272 amino acids and features a modular extracellular architecture. The Sushi 1 domain extends from amino acids 22 to 84, forming part of the IL-2 binding interface. A disordered region spans amino acids 87 to 123, providing flexibility between structured domains. The Sushi 2 domain occupies amino acids 123 to 186, contributing additional binding contacts. Another disordered region from amino acids 190 to 212 precedes the transmembrane segment. These sushi domains, also called complement control protein modules, adopt characteristic beta-sandwich folds that interact with IL-2 and stabilise the receptor complex.
Key variants
Genetic variation in IL2RA includes both common polymorphisms and rare variants affecting protein expression or function. Common variants in regulatory regions have been associated with altered CD25 expression levels on immune cells, particularly regulatory T cells. These expression quantitative trait loci may influence autoimmune disease susceptibility through effects on immune tolerance mechanisms. Rare coding variants that disrupt receptor function have been described in immunodeficiency contexts, though such alterations are uncommon.
Sample of pathogenic variants
9 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.301C>T | p.Gln101Ter | Pathogenic | ★★☆☆ | Immunodeficiency due to CD25 deficiency |
c.130G>T | p.Gly44Ter | Pathogenic | ★☆☆☆ | Immunodeficiency due to CD25 deficiency |
c.166del | p.Arg56fs | Pathogenic | ★☆☆☆ | Immunodeficiency due to CD25 deficiency |
c.227G>A | p.Trp76Ter | Pathogenic | ★☆☆☆ | Immunodeficiency due to CD25 deficiency |
c.246C>A | p.Cys82Ter | Pathogenic | ★☆☆☆ | Immunodeficiency due to CD25 deficiency |
c.368-2A>G | - | Pathogenic | ★☆☆☆ | not provided |
c.122A>C | p.Tyr41Ser | Pathogenic | - | Immunodeficiency due to CD25 deficiency |
c.497G>A | p.Ser166Asn | Pathogenic | - | Immunodeficiency due to CD25 deficiency |
c.692dup | p.Thr232fs | Pathogenic | - | Immunodeficiency due to CD25 deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
IL2RA variants have been associated with increased susceptibility to several autoimmune conditions through genome-wide association studies. Research has identified associations with type 1 diabetes mellitus, where altered IL-2 signalling may affect pancreatic beta-cell tolerance. The gene has also been linked to multiple sclerosis, suggesting a role in central nervous system autoimmunity. Additionally, variants have been associated with alopecia areata, an autoimmune condition affecting hair follicles. These associations typically reflect small effect sizes consistent with polygenic architecture, where multiple genes collectively influence disease risk.
- Alopecia areata
- Multiple sclerosis
- Type 1 diabetes mellitus Dedicated page coming soon
UK clinical status
Within the NHS Genomic Medicine Service, IL2RA appears on several clinical panels with green (high evidence) ratings. The gene is included in the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), reflecting its role in immune regulation. It also features on the Neonatal diabetes panel (R143), the Infantile enterocolitis & monogenic inflammatory bowel disease panel, and the Gastrointestinal epithelial barrier disorders panel. Additionally, IL2RA has been included in COVID-19 research panels, highlighting interest in immune response modulation during viral infection.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of IL2RA in the immune system?
IL2RA encodes the alpha chain of the interleukin-2 receptor, which enables immune cells to respond to IL-2 signalling. This is particularly important for regulatory T cells that maintain immune tolerance and prevent the immune system from attacking the body's own tissues.
How do IL2RA variants influence autoimmune disease risk?
Common variants in IL2RA regulatory regions can alter the expression levels of the receptor on immune cells, potentially affecting the balance between immune activation and tolerance. These variants typically contribute small individual effects as part of a broader polygenic risk architecture involving many genes.
Is IL2RA testing available through the NHS?
IL2RA is included on several NHS Genomic Medicine Service panels, particularly for primary immunodeficiency, monogenic inflammatory bowel disease, and neonatal diabetes. Testing is typically arranged through specialist clinics when clinical features suggest a relevant monogenic condition, rather than for common autoimmune disease risk assessment.