Alternative titles; symbols
HGNC Approved Gene Symbol: IL2RB
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:37,125,838-37,175,118 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Immunodeficiency 63 with lymphoproliferation and autoimmunity | 618495 | Autosomal recessive | 3 |
The IL2RB gene encodes the beta subunit of the interleukin-2 (IL2) receptor, which transmits signals from the cytokines IL2 (147680) and IL15 (600554). IL2RB shows constitutive or induced expression on various types of immune cells, including CD4+ T regulatory cells, CD4+ and CD8+ T cells, B cells, and NK cells (summary by Zhang et al., 2019).
Tsudo et al. (1989) characterized the interleukin-2 receptor beta chain using 3 monoclonal antibodies, designated Mik-beta1, -beta2, and -beta3. They showed by immunoprecipitation that the beta chain has a molecular mass of 68,000-72,000 Da. Moreover, they found that the beta chain was expressed on the surface of peripheral blood Leu-19+ natural killer cells in the absence of alpha-chain expression. Also see IL2RA (147730).
Gnarra et al. (1990) characterized the IL2RB gene. They found that the IL2 receptor is present in 3 forms with respect to binding ability to IL2 (147680): high, intermediate, and low affinity forms. The alpha chain constitutes the low affinity form and is not functional in IL2 internalization and signal transduction. The beta chain by itself constitutes the intermediate affinity form. Hatakeyama et al. (1989) presented evidence that coexpression of the IL2RA and IL2RB genes results in the high affinity form of the receptor.
Giri et al. (1994) showed that IL2RB and IL2RG (308380), but not IL2RA, transduce signals by IL15 (600554) in addition to IL2.
Kondo et al. (2000) showed that a clonogenic common lymphoid progenitor, a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B, and natural killer cells), can be redirected to the myeloid lineage by stimulation through exogenously expressed interleukin-2 receptor and GMCSF receptor (138981, 306250). Analysis of mutants of the beta chain of the IL2 receptor revealed that the granulocyte and monocyte differentiation signals are triggered by different cytoplasmic domains, showing that the signaling pathways responsible for these unique developmental outcomes are separable. Finally, Kondo et al. (2000) showed that the endogenous myelomonocytic cytokine receptors for GM-CSF and macrophage colony-stimulating factor (CSF1R; 164770) are expressed at low to moderate levels on the more primitive hematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL2. Kondo et al. (2000) concluded that cytokine signaling can regulate cell fate decisions and proposed that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.
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.
Using flow cytometry, Corrigall et al. (2001) detected expression of a functional IL2R of intermediate affinity composed solely of IL2RB and IL2RG on fibroblast-like synoviocytes (FLS) obtained from rheumatoid arthritis and osteoarthritis patients. Addition of recombinant IL2, IL1B (147720), or TNFA (191160) independently did not upregulate expression of the receptors on FLS, but IL2 or IL1B did significantly increase expression of intracellular tyrosine-phosphorylated proteins and the production of MCP1 (158105). Corrigall et al. (2001) proposed that MCP1 in the synovial membrane serves to recruit macrophages and perpetuate inflammation in the joints of patients with rheumatoid arthritis.
Dai et al. (2010) noted that CD8 (see 186910)-positive/CD122-positive T cells have been shown to function, paradoxically, as both regulatory and memory T cells. Using flow cytometric analysis, they demonstrated that mouse Cd8-positive/Cd122-positive T cells included both Pd1 (PDCD1; 600244)-positive and Pd1-negative subpopulations. Only the Pd1-positive subpopulation suppressed T-cell responses in vitro and in vivo, and this suppression occurred largely in an Il10 (124092)-dependent manner. Il10 production, in turn, was dependent on costimulatory signaling of both Cd28 (186760) and Pd1. Cd8-positive/Cd122-positive/Pd1-negative T cells mediated skin graft rejection. Dai et al. (2010) concluded that CD8-positive/CD122-positive T cells can be either regulatory or memory T cells, depending on their PD1 expression and antigen specificity.
Crystal Structure
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.
Shibuya et al. (1990) found that the IL2RB gene contains 10 exons spanning about 24.3 kb and that the gene product is encoded by exons 2-10. The cysteine-rich extracellular region, which displays a significant evolutionary resemblance to other cytokine receptors, as well as to growth hormone and prolactin receptors, is encoded primarily by exons 3 and 4.
By Southern analysis of somatic cell hybrid DNA and in situ hybridization, Gnarra et al. (1990) localized the IL2RB gene to chromosome 22q11.2-q12, a region that is associated with several lymphoid neoplasias. By RFLP linkage analysis, Shibuya et al. (1990) assigned the IL2RB gene to 22q12-q13. By in situ hybridization, Campbell et al. (1992) mapped the Il2rb gene to band E of mouse chromosome 15.
In 2 sibs, born of consanguineous parents from Tajikistan, with immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63; 618495), Fernandez et al. (2019) identified a homozygous 9-bp in-frame deletion in the IL2RB gene, resulting in the deletion of 3 conserved residues in the extracellular motif (146710.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient NK and T cells cells showed markedly decreased surface expression of IL2RB compared to controls. Plasma levels of both IL2 and IL15 were increased, reflecting impaired receptor responses, and this was associated with variably increased amounts of phosphorylated STAT5 (601511) in NK and T cells compared to controls. The findings were consistent with dysregulated IL2/IL15 signaling and indicated immune cell-type-specific responses to the mutation.
In 8 patients from 4 consanguineous pedigrees with IMD63, Zhang et al. (2019) identified 3 different homozygous mutations in the IL2RB gene: a missense mutation (L77P; 146710.0002), which caused a hypomorphic effect depending on cell type; a different missense mutation (S40L; 146710.0003), which impaired the response to IL2; and a nonsense mutation (Q96X; 146710.0004), which resulted in a complete loss of function. The sibs with the Q96X variant had the most severe phenotype, resulting in a prenatal phenotype and death soon after birth. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Patient-derived CD4+ and CD8+ T cells and HEK293 cells expressing the mutations showed variable but specific impairments in downstream IL2 signaling with decreased STAT5 phosphorylation compared to controls. Transfection of wildtype IL2RB in T cells from patients with the L77P mutation partially rescued the impaired IL2 response. Zhang et al. (2019) noted that different immune cells responded differently to the molecular defect.
Suzuki et al. (1995) generated mice defective in Il2rb expression by insertion of a neomycin resistance cassette into the IL2RB gene at exon 6, which encodes a region of the extracellular domain proximal to the transmembrane region. Mice from 2 independent embryonic stem cell lines were separately bred homozygous for the defect, with both lineages showing identical gross appearances. The mice showed normal growth until approximately 3 weeks after birth. After 4 weeks of age, they were generally smaller than normal or heterozygous littermates and had abnormal appearances characterized by fuzzy hair, slow movement, and fully developed external genitals. Death occurred at approximately 12 weeks. In mice lacking the IL2R beta chain, T cells were shown to be spontaneously activated, resulting in exhaustive differentiation of B cells into plasma cells and the appearance of high serum concentrations of immunoglobulins G1 and E, as well as autoantibodies that cause hemolytic anemia. Marked infiltrated granulocytopoiesis was also apparent. Depletion of CD4+ T cells in mutant mice rescued B cells without reversion of granulocyte abnormalities. T cells did not proliferate in response to polyclonal activators, nor could antigen-specific immune responses be elicited. Thus, Suzuki et al. (1995) concluded that Il2rb is required to keep the activation programs of T cells under control, to maintain homeostasis, and to prevent autoimmunity.
In 2 sibs, born of consanguineous parents from Tajikistan, with immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63; 618495), Fernandez et al. (2019) identified a homozygous 9-bp deletion (c.665_673del, NM_000878.3) in the IL2RB gene, resulting in the in-frame deletion of 3 conserved residues in the extracellular motif. The authors referred to the consequence on the protein both as pro222_gln225del and pro222_ser224del. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient NK and T cells cells showed markedly decreased surface expression of IL2RB compared to controls. Plasma levels of both IL2 (147680) and IL15 (600554) were increased, and this was associated with increased amounts of phosphorylated STAT5 (601511) compared to controls.
In 3 patients from 2 unrelated consanguineous families (family A of Pakistani descent and family B of Bengali descent), with immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63; 618495), Zhang et al. (2019) identified a homozygous mutation (chr22.37,538,526A-G, GRCh37) in exon 4 of the IL2RB gene, resulting in a leu77-to-pro (L77P) substitution in the extracellular D1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant was not found in the dbSNP, Exome Sequencing Project, or ExAC databases, but had a very low frequency in the gnomAD database. Patient CD4+ and CD8+ T cells and NK cells had significantly decreased surface expression of IL2RB compared to controls; however, cytosolic levels of IL2RB were increased, suggesting that the mutation caused misfolding and improper trafficking of the protein. In vitro expression studies in HEK293 cells confirmed that the L77P mutant protein was sequestered abnormally within the cell, but retained some response to IL2 stimulation, consistent with a hypomorphic effect. In particular, patient T cells showed decreased IL2-mediated signaling, whereas NK cells retained signaling and cytotoxic capacity. Transduction of wildtype IL2RB into patient T cells was able to partially rescue STAT phosphorylation in response to IL2. The findings indicated that the mutation has different effects depending on cell type.
In 2 patients from a consanguineous Saudi kindred (family C) with immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63; 618495), Zhang et al. (2019) identified a homozygous mutation (chr22.37,539,634C-T, GRCh37) in the IL2RB gene, resulting in a ser40-to-leu (S40L) substitution at a putative IL2-binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, Exome Sequencing Project, ExAC databases, or gnomAD databases. In vitro functional expression studies in HEK293 cells showed that surface expression of S40L was decreased somewhat compared to controls, but had no response to IL2 stimulation. Molecular modeling was consistent with the mutation causing decreased binding of IL2 to IL2RB.
In 3 sibs, conceived of consanguineous Romany parents (family D), with immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63; 618495), Zhang et al. (2019) identified a homozygous mutation (chr22.37,537,259G-A, GRCh37) in the IL2RB gene, resulting in a gln96-to-ter (Q96X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, Exome Sequencing Project, ExAC databases, or gnomAD databases. Patient thymic tissue showed absence of IL2RB expression, consistent with a complete loss of function. In vitro expression studies in HEK293 cells confirmed that the mutation had no response to IL2 stimulation, causing a complete loss of function. One patient died in the neonatal period, whereas the other 2 affected fetuses were terminated in utero.
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