Alternative titles; symbols
HGNC Approved Gene Symbol: IL2RA
Cytogenetic location: 10p15.1 Genomic coordinates (GRCh38): 10:6,010,689-6,062,367 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p15.1 | {Diabetes, mellitus, insulin-dependent, susceptibility to, 10} | 601942 | 3 | |
| Immunodeficiency 41 with lymphoproliferation and autoimmunity | 606367 | Autosomal recessive | 3 |
The IL2RA gene encodes the alpha subunit of the cell surface receptor for the T-cell growth factor interleukin-2 (IL2; 147680). The IL2 receptor is a heterotrimer of IL2RA, IL2RB (146710), and IL2RG (308380) and plays a vital role in maintaining the immune system. IL2RA is constitutively expressed on regulatory T cells (Tregs) and is involved in both tolerance regulation and T-cell expansion (summary by Goudy et al., 2013). IL2RA contributes only to the binding affinity of IL2, but not to the recruitment of signaling molecules (summary by Bezrodnik et al., 2014).
Leonard et al. (1983) used a monoclonal antibody for T cell growth factor to characterize the IL2 receptor.
Leonard et al. (1984), Nikaido et al. (1984), and Cosman et al. (1984) cloned the IL2R gene. Leonard et al. (1984) identified 1 gene but 2 IL2R mRNAs that differ in their polyadenylation signals. They also isolated an additional cDNA that may correspond to an alternatively spliced mRNA that lacks a 216-bp segment and appears to encode an altered membrane protein that cannot bind interleukin-2. Nikaido et al. (1984) determined the primary structure of the precursor, which has 272 amino acid residues.
Hatakeyama et al. (1985) provided evidence that the IL2 receptor is generated, at least in part, by a single gene, namely, the gene encoding Tac antigen (p55). Hatakeyama et al. (1986) used site-directed mutation in the Tac antigen cDNA to generate a mutant receptor. Results of expression studies led them to propose that a molecule that is associated with but distinct from the Tac antigen is involved in the regulation of the functional IL2R complex. Tsudo et al. (1986) arrived at a similar conclusion on the basis of other studies.
Robb et al. (1988) employed further cytomutagenesis studies of the Tac molecule to derive a correlation between the structure and function of various components of the molecule. The Tac antigen represents the alpha chain of IL2R, which binds IL2 with low affinity (Leonard et al., 1984; Nikaido et al., 1984), whereas the beta chain by itself does not bind IL2 when expressed in COS-7 cells. However, coexpression of the 2 chains leads to the formation of a high-affinity receptor. The same situation exists with the alpha and beta chains of the GM-CSF receptor (CSF2RA; 306250).
Leonard et al. (1985) reported that the IL2R gene has 8 exons spanning more than 25 kb. Ferrari et al. (1987) determined that exons 2 and 4 are derived from a gene duplication event and also are homologous to the recognition domain of factor B of the complement system (CFB; 138470).
Leonard et al. (1985) mapped the IL2R gene to 10p15-p14. Ferrari et al. (1987) confirmed the assignment of IL2R to chromosome 10 by studies of DNA from a rodent-human hybrid panel. By in situ hybridization, Webb et al. (1990) assigned the Il-2ra gene to band A2-A3 of mouse chromosome 2.
Crystal Structure
Rickert et al. (2005) presented the 2.8-angstrom crystal structure of a complex between human IL2 (147680) and IL2RA, which interact in a docking mode distinct from that of other cytokine receptor complexes. IL2RA is composed of strand-swapped 'sushi-like' domains, unlike the classical cytokine receptor fold. As a result of this domain swap, IL2RA uses a composite surface to dock into a groove on IL2 that also serves as a binding site for antagonist drugs.
Wang et al. (2005) reported the crystal structure of the quaternary complex of IL2 with IL2RA, IL2RB, and IL2RG at a resolution of 2.3 angstroms.
Lamaze et al. (2001) selectively blocked clathrin (see 118960)-dependent endocytosis using dominant-negative mutants of EPS15 (600051) and showed that clathrin-mediated endocytosis of transferrin (190000) was inhibited, while endocytosis of the IL2Rs proceeded normally. Ultrastructural and biochemical experiments showed that clathrin-independent endocytosis of IL2Rs exists constitutively in lymphocytes and is coupled to their association with detergent-resistant membrane domains. The authors found that clathrin-independent endocytosis requires dynamin (see 602377) and is specifically regulated by Rho family GTPases (see 604980). These results defined novel properties of receptor-mediated endocytosis and established that IL2R is efficiently internalized through this clathrin-independent pathway.
Ihle and Kerr (1995) reviewed the activation cascade involving cytokines, IL2RA and other cytokine receptors, the Janus kinases (see JAK1; 147795), and the signal transducers and activators of transcription, or STATs (see STAT1; 600555).
In a commentary, Shevach (2001) noted that the transfer into immunocompromised mice of CD4 (186940)-positive T cells from which a subpopulation coexpressing CD25 had been removed induced organ-specific autoimmune disease in most recipients (Asano et al., 1996). The CD4-positive/CD25-positive population was solely responsible for the prevention of this autoimmunity. Shevach (2001) cited a number of publications that had confirmed the importance of these cells in the regulation of immune responses in human models. All the studies appeared to show that the suppression involves a cell contact-dependent, cytokine-independent mechanism after activation of the CD4-positive/CD25-positive T cells.
Due to similarities between the autoimmunity and inflammation produced by manipulation of CD25-positive/CD4-positive regulatory T (Tr) cells and those induced by genetic defects in the FOXP3 gene (300292), Hori et al. (2003) investigated the contribution of Foxp3 to the development and/or function of Tr cells in mice. RT-PCR analysis of normal mice showed stable, constitutive expression of Foxp3 that was high in Tr cells, low in CD4-positive/CD25-negative cells, and absent in CD4-negative/CD8-positive T cells. Transduced expression of Foxp3 in CD4-positive/CD25-negative cells imparted a Tr phenotype in these cells, with low levels of cytokine expression, compared with nontransduced or vector-only transduced cells, and high levels of CD103 (604682), GITR (TNFRSF18; 603905), and CTLA4 (123890). Transduced cells also showed cell-cell contact suppressive activity in vitro, as well as suppression of autoimmunity and inflammation in vivo. Hori et al. (2003) proposed that FOXP3 may be a master regulatory gene and a more specific marker of Tr cells than other cell surface molecules. They also suggested that FOXP3 transduction could be a therapeutic mode for the treatment of inflammatory diseases.
Pasare and Medzhitov (2003) found that microbial induction of dendritic cell (DC) maturation by activation of Toll-like receptors (e.g., TLR4; 603030) abrogated the suppressive effects of CD25-positive/CD4-positive Tr cells. The blockade of Tr cell-mediated suppression was independent of costimulatory molecule expression on DCs. Stimulation of the TLR/MYD88 (602170) pathway in DCs led to the expression of IL6 (147620) and, most likely, other secreted factors that do not signal through the common gamma chain (IL2RG; 308380), and these mediated the block of suppression. Il6-deficient mice were severely compromised in the induction of effector T-cell responses, and this defect could be transiently overcome by depletion of Tr cells. Pasare and Medzhitov (2003) concluded that the failure of Il6-deficient mice to overcome Tr-mediated suppression resulted in increased susceptibility to infection and resistance to autoimmunity. In a commentary, Powrie and Maloy (2003) proposed a model for the control of Tr development by innate immune cells and noted that the targeting of IL6 may be an attractive treatment for inflammatory diseases.
T follicular helper (Tfh) cells are a subset of CD4-positive T cells that express CXCR5 (601613) and are important in supporting plasma cell and germinal center responses. Using immunohistochemical and flow cytometric analyses, Li et al. (2016) found that Tfh-cell differentiation in mice depended on Ebi2 (GPR183; 605741) and its ligand, 7-alpha,25-dihydrocholesterol, to mediate positioning of activated Cd4-positive T cells at the interface of the follicle and the T-cell zone. At this location, activated T cells interacted with activated DCs and were exposed to Tfh cell-promoting Icoslg (605717). Activated DCs in the outer T zone further augmented Tfh-cell differentiation by producing membrane and soluble forms of Cd25, which quenched T cell-derived Il2. Mice lacking Ebi2 in T cells or Cd25 in DCs had reduced Tfh cells and mounted defective T cell-dependent plasma cell and germinal center responses. Li et al. (2016) concluded that EBI2 augments Tfh-cell fate by promoting interaction with DCs and that DC-derived CD25 controls IL2 availability and T-cell differentiation.
Simeonov et al. (2017) identified several CRISPR activation-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbors an autoimmunity risk variant, rs61839660. Using engineered mouse models, Simeonov et al. (2017) found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a proinflammatory T helper (TH17) cell state and away from a regulatory T cell state.
Immunodeficiency 41 with Lymphoproliferation And Autoimmunity
In a patient with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367), Sharfe et al. (1997) identified a homozygous 4-bp deletion in the CD25 gene, resulting in a frameshift in protein translation (147730.0001).
In an 8-year-old Caucasian boy with IMD41, Caudy et al. (2007) identified compound heterozygous truncating mutations in the IL2RA gene (147730.0004 and 147730.0005). Each unaffected parent was heterozygous for 1 of the mutations.
In an 8-year-old girl, born of consanguineous Italian parents, with IMD41, Goudy et al. (2013) identified a homozygous missense mutation in the IL2RA gene (S166N; 147730.0006). Each unaffected parent was heterozygous for the mutation. Patient CD4+ T cells showed absence of surface IL2RA expression, consistent with a loss of function. However, IL2RA was detected within the cytoplasm of the patient's T cells, suggesting that the mutation inhibits membrane expression. Additional functional studies of the variant were not performed.
In an adopted 5-year-old girl from Argentina with IMD41, Bezrodnik et al. (2014) identified a homozygous missense mutation in the IL2RA gene (Y41S; 147730.0007). Functional studies of the variant were not performed, but patient CD4+ T lymphocytes did not show upregulation of IL2RA upon activation.
Type 1 Diabetes Mellitus 10
By using a haplotype tag SNP approach, Vella et al. (2005) tested type 1 diabetes sample collections consisting of 7,457 cases and controls and of 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. They found strong statistical evidence in the case-control collection for a type 1 diabetes locus in the CD25 region of chromosome 10p15 (IDDM10; 601942) and replicated the association in the family collection. Vella et al. (2005) recognized that association might not be with CD25 itself, but rather with a causal variant in linkage disequilibrium with CD25.
In an analysis of up to 5,312 individuals with type 1 diabetes and 6,855 controls, Lowe et al. (2007) localized the type 1 diabetes association in the IL2RA gene region to 2 independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5-prime regions of IL2RA and flanking gene RBM17 (606935) (odds ratio = 2.04; P = 10(-28)). IL2RA type 1 diabetes susceptibility genotypes were associated with lower circulating levels of soluble IL2RA (p = 6.28 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to type 1 diabetes.
Associations Pending Confirmation
For discussion of a possible association between variation in the IL2RA gene and multiple sclerosis, see MS2 (612594).
In a patient with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367), who was subsequently treated with allogeneic bone marrow transplantation, Sharfe et al. (1997) found homozygosity for a 4-bp deletion in the IL2RA gene at nucleotides 60 to 64, resulting in a translational frameshift. Translation proceeded for 20 amino acids before the deletion and resultant frameshift occurred, effectively ablating CD25 expression. A further 25 irrelevant amino acids were added before termination. The homozygous nature of the mutation was confirmed by analysis of sequences from the parents, who both demonstrated a normal and a 4-bp-deleted allele.
In an analysis of 5,312 individuals with type 1 diabetes (IDDM10; 601942) and 6,855 controls, Lowe et al. (2007) found that a SNP in the IL2RA gene, {dbSNP ss52580101}, was the most associated SNP in a 40-kb region encompassing IL2RA intron 1 and the 5-prime regions of IL2RA and RBM17 (606935) (P = 3.37 x 10(-20)). The submitted SNP {dbSNP ss52580101} has been assigned the refSNP identifier rs41295061.
Lowe et al. (2007) found by logistic regression analysis that a SNP in intron 1 of IL2RA, rs11594656, added significantly to the effect of {dbSNP ss52580101} (147730.0002) on susceptibility to type 1 diabetes (IDDM10; 601942) (P = 8.19 x 10(-7)). Determination of soluble IL2RA concentration (sIL2RA) for 1,357 case plasma samples found significant association of rs11594656 with sIL2RA (P = 2.15 x 10(-23)). The presence of 2 copies of the susceptibility allele (T) was associated with lower concentrations of sIL2RA compared with the presence of 1 or more copies of the protective allele (A).
In a boy with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367), Caudy et al. (2007) identified compound heterozygous truncating mutations in the IL2RA gene: a 1-bp insertion (c.692ins), resulting in a frameshift and premature termination, and a c.301C-T transition (147730.0005), resulting in a stop codon and nonsense-mediated mRNA decay. Each mutation was inherited from an unaffected parent. Patient lymphocyte cells showed complete absence of IL2RA expression, consistent with a loss of function. Parental lymphocytes showed about half the amount of CD25 on the cell surface during T-cell activation. Patient T cells showed poor proliferation in response to IL2, but this effect could be rescued by high doses of IL2 or IL15 (600554), indicating that the rest of the downstream signaling pathway was intact. The patient had recurrent infections from infancy, and immunologic studies showed defective IL10 (124092) expression from CD4+ T cells. The findings indicated that IL2 responsiveness is important for IL10 production from CD4+ cells.
For discussion of the c.301C-T mutation in the IL2RA gene that was found in compound heterozygous state in a boy with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367) by Caudy et al. (2007), see 147730.0004.
In an 8-year-old girl, born of consanguineous Italian parents, with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367), Goudy et al. (2013) identified a homozygous c.497G-A transition in exon 4 of the IL2RA gene, resulting in a ser166-to-asn (S166N) substitution. Each unaffected parent was heterozygous for the mutation. Patient CD4+ T cells showed absence of surface IL2RA expression, consistent with a loss of function. However, IL2RA was detected within the cytoplasm of the patient's T cells, suggesting that the mutation inhibits membrane expression. Additional functional studies of the variant were not performed.
In an adopted 5-year-old girl from Argentina with immunodeficiency-41 with lymphoproliferation and autoimmunity (IMD41; 606367), Bezrodnik et al. (2014) identified a homozygous c.122A-C transversion in the IL2RA gene, resulting in a tyr41-to-ser (Y41S) substitution in the extracellular domain of the protein. Functional studies of the variant were not performed, but patient CD4+ T lymphocytes did not show upregulation of IL2RA upon activation.
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