IL7R (interleukin 7 receptor)

2013-08-01   Daniel Ribeiro , João T Barata 

Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Identity

HGNC
LOCATION
5p13.2
LOCUSID
ALIAS
CD127,CDW127,IL-7R-alpha,IL7RA,ILRA
FUSION GENES

DNA/RNA

Atlas Image
IL7R gene. The gene is composed of 8 exons highlighted in dark green. The 5 and 3 untranslated regions (UTR) are highlighted in light green.

Transcription

The gene is composed of 8 exons. The canonical transcript is 4619 bp long. Alternative splicing generates a soluble isoform lacking exon 6 and introducing a premature stop codon (Goodwin et al., 1990; Rose et al., 2009).

Pseudogene

No pseudogene.

Proteins

Atlas Image
IL-7Rα protein. This receptor belongs to the type-I cytokine receptor family. In the extracellular domain, it displays 4 paired cysteines (represented in yellow) in 2 fibronectin type III-like domains and, closer to the transmembrane domain, a WSxWS motif. The intracellular domain has a Box 1 motif and at least 2 tyrosines (Y401, Y449) involved in signal transduction (Lin et al., 1995; Venkitaraman and Cowling, 1994).

Description

The precursor IL-7Rα protein includes a signal peptide (20 aminoacids) and has 459 aminoacids in total. The mature protein undergoes several post-translational modifications including glycosylation (6 potential N-glycosylation sites in the extracellular domain) and dissulfide bond formation. The extracellular domain has 219 aminoacids (spanning from aminoacids 21 to 239), the transmembrane domain has 25 aminoacids (spanning from aminoacids 240 to 264), and the cytoplasmic tail spans from aminoacids 265 - 459 (195 aminoacids). The soluble isoform of the receptor lacks the transmembrane domain (exon 6) and, due to an altered translation reading frame, it thereafter contains 27 unique aminoacids in the C-terminus (Goodwin et al., 1990; Rose et al., 2009).

Expression

IL-7Rα expression and signaling is required for normal T-cell development and homeostasis (Puel et al., 1998; Ribeiro et al., 2013). Although IL-7 signaling is not required for normal human B-cell development (in contrast to the mouse, where it is fundamental) IL-7Rα is also expressed in B-cell precursors (Mazzucchelli and Durum, 2007).

Localisation

The functional protein is localized at the plasma membrane where it forms an heterodimeric complex with the common gamma chain (IL-2Rγ, CD132) to transduce IL-7 signaling or the cytokine receptor-like factor 2/ thymic stromal lymphopoietin receptor (CRLF2/TSLPR) to transduce TSLP signaling. IL-7Rα endocytosis via clathrin-coated pits appears to be required for maximal IL-7-mediated signaling (Henriques et al., 2010).

Function

IL-7Rα mediates the signaling of IL-7 and TSLP cytokines. The cytoplasmic tail of IL-7R associates directly with JAK1 to transduce intracellular signaling together with JAK3 or JAK2 that are associated with the IL-2Rγ or TSLPR, respectively. The intracellular signaling pathways activated upon IL-7/IL-7R engagement in T-cells are the JAK/STAT (Lin et al., 1995; Rosenthal et al., 1997), PI3K/Akt/mTOR (Dadi and Roifman, 1993; Venkitaraman and Cowling, 1994; Rathmell et al., 2001) and, in some instances, MEK/Erk (Fleming and Paige, 2001; Maki and Ikuta, 2008; Patel and Chang, 2012).
IL-7/IL-7R signaling is required for T-cell development at different stages. At the double-negative stage (DN; CD4- CD8-), it is required for survival and proliferation of T-cells. It is also required to initiate the recombination of the TCRγ locus (Ye et al., 2001), the reason why it is absolutely required for γδ T-cell development. The receptor is down-regulated at the double-positive stage (DP; CD4+ CD8+) and up-regulated again at the single-positive stage (SP; CD4+ or CD8+). At this stage, IL-7R appears to be involved in CD4 versus CD8 lineage specification (at least in the mouse, possibly in humans) and overall cell survival (Park et al., 2010; Sinclair et al., 2011). Mature T-cells also benefit from IL-7R signaling for homeostatic maintenance and function (Soares et al., 1998).
The function of the TSLP/IL-7R signaling is much less known. Most studies, suggest an important role in the normal function of dendritic cells, immune tolerance and allergy (Watanabe et al., 2005; Lee et al., 2008; reviewed in Ziegler, 2012 and Hanabuchi et al., 2012).

Homology

IL-7R displays aminoacid sequence identity with other human cytokine receptors, such as IL-2R (14.6%), IL-6R (13.2%) GM-CSF receptor (16.0%) GH receptor (12.9%) (Goodwin et al., 1990).
Orthologs of the human IL-7R are found in other species. The murine Il7r has 64%/67.2% DNA/protein identity (Goodwin et al., 1990) and the zebrafish il7r has 20.5% protein identity (Liongue and Ward, 2007) compared with the human receptor.

Mutations

Atlas Image
IL-7Rα mutational hotspot for gain-of-function mutations. The figure depicts the 3 major domains of the IL-7R with the mutational hotspots present. The T-ALL mutations are restricted to exon 6 (coding for the transmembrane domain) and affect the juxtamembrane-transmembrane region (yellow lightning bolts). B-ALL mutations, although rarer, can also affect exon 5 (S185C; red lightning bolt).

Germinal

Hereditary recessive inactivating mutations in the IL7R gene have been found to cause severe combined immunodeficiency (SCID)(Puel et al., 1998; Roifman et al., 2000; Jo et al., 2004; Giliani et al., 2005). The mutations occur in the extracellular domain coding region and comprise missense, nonsense mutations and splicing affecting mutations. The IL-7R SCID is characterized as T-B+NK+. The treatment is hematopoietic stem cell transplantation.

Somatic

Somatic and heterozygous IL7R gain-of-funtion gene mutations have been found in around 9-10% of childhood T-cell acute lymphoblastic leukemia (T-ALL) cases (Zenatti et al., 2011; Shochat et al., 2011; Zhang et al., 2012). Later, mutations in the IL7R in adult T-ALL (1.7%) were also found (Kim et al., 2013). So far, all T-ALL mutations described are restricted to exon 6, affecting the extracellular juxtamembrane-transmembrane domain of the protein. The mutations are in-frame insertions or deletions-insertions. The majority include an unpaired cysteine addition responsible for the homodimerization of two IL7-Rα chains via disulphide bond formation. The dimerization of the receptor leads to ligand-independent constitutive signaling via JAK1 (Zenatti et al., 2011), contrasting with the physiological heterodimeric IL-7-dependent activation of the receptor that additionally requires IL-2Rγ and JAK3.
IL7R somatic, heterozygous mutations have also been described in a small fraction of B-cell ALL (B-ALL) cases (less than 1%), significantly associated with aberrant TSLPR expression (Shochat et al., 2011). These included similar mutations to those found in T-ALL, as well as, in half of the cases, mutations in exon 5 leading to an S185C aminoacid substitution (Shochat et al., 2011).

Implicated in

Entity name
Severe combined immunodeficiency (SCID)
Disease
IL-7R SCID of T-B+NK+ type results from loss-of-function mutations. For further details see the Mutations section.
Prognosis
IL-7R SCID is a fatal disease. The treatment is bone marrow transplantation.
Prognosis
IL7R mutations are not associated with prognosis (Zenatti et al., 2011). Increased IL-7 responsiveness in vitro was associated with better initial response to treatment in vivo (Karawajew et al., 2000). Low expression of IL-7R was found correlated with poor prognosis (Cleaver et al., 2010).
Oncogenesis
IL-7/IL-7R signaling has a major impact in the survival and proliferation of T-ALL cells in vitro (e.g. Touw et al., 1990; Dibirdik et al., 1991; Barata et al., 2004a; Barata et al., 2004b) and leukemia expansion in vivo (Silva et al., 2011).
Oncogenic IL7R activating mutations occur in T-ALL. See the Mutations section for details.
Truncated forms of the IL-7R originated by alternative splicing were found in childhood T-ALL primary samples (Korte et al., 2000). The truncated receptors still bind IL-7 and it was postulated, but not functionally demonstrated, that they might modulate IL-7 downstream signaling.
Entity name
B-cell acute lymphoblastic leukemia (B-ALL)
Oncogenesis
IL-7R mutations occur in B-ALL. See the Mutations section for details.
Expression of survival and proliferation markers is associated with CD127+ B-ALLs vs CD127- B-ALLs (Sasson et al., 2010).
Entity name
Chronic lymphocytic leukemia (CLL)
Oncogenesis
IL-7 mRNA was detected in a whole cohort of 20 CLL primary samples (Frishman et al., 1993).
IL-7 was found to induce proliferation of CLL primary samples (Digel et al., 1991).
Entity name
Oncogenesis
IL-7 was found to induce proliferation of AML primary samples (Digel et al., 1991).
An Exon 6 mutation in the IL7R gene was found in one case of adult AML (Kim et al., 2013). The functional impact of this mutation, which does not conform to the T-ALL or B-ALL type of mutations, was not evaluated.
Entity name
Oncogenesis
Both IL-7 and IL-7R proteins were found to be expressed in HL cell lines. An IL-7 autocrine loop was present that could sustain basal proliferation of these cells and the cells could further respond to exogenous added IL-7 (Cattaruzza et al., 2009).
Entity name
Oncogenesis
Both IL-7 and IL-7R expression was found in CTL primary samples (Foss et al., 1994). All 7 samples analyzed proliferated in the presence of IL-7. There was evidence for a possible autocrine loop.
Entity name
Breast cancer
Oncogenesis
Both IL-7 and IL-7R were found to be expressed in some breast cancer cases. Patients with poorer prognosis had higher expression of both genes in the cancer tissue than those with better prognosis (Al-Rawi et al., 2004).
Entity name
Colorectal cancer
Oncogenesis
IL-7 was found to be secreted in vitro by cultured colorectal cancer cell lines (2/4) and primary samples (16/18) (Maeurer et al., 1997).
Mutations in the exon 6 of the IL7R (0.5%) were found in a cohort of primary samples (Kim et al., 2013). However, these were frameshift mutations generating an early stop codon. Their functional impact was not evaluated.
Entity name
Esophageal cancer
Oncogenesis
The expression levels of a small array of 21 cytokines in 6 esophageal cancer cell lines showed that IL-7 is expressed in 5 (Oka et al., 1995). Whether the IL-7R is also expressed remains to be investigated.
Entity name
Renal carcinoma
Oncogenesis
Both IL-7 mRNA and protein were found to be secreted in renal carcinoma cell lines dependent on interferon gamma (IFNg) constitutive stimulation (Trinder et al., 1999).
In another study, IL-7R mRNA was found expressed in 2/7 renal carcinoma cell lines (Cosenza et al., 2002).
Entity name
Lung cancer
Prognosis
High expression of IL-7R in tumor cells isolated from patients with stage I lung adenocarcinoma was predictive of poor overall outcome and increased probability of tumor recurrence (Suzuki et al., 2013).
Oncogenesis
IL-7R mRNA and protein (3/7) were detected in lung cancer cell lines (Cosenza et al., 2002).
A missense mutation in the exon 6 of the IL7R was found in a member (0.6%) of a cohort of primary non-small cell lung cancer samples (Kim et al., 2013). The mutation does not conform to the type of mutations found in T-ALL or B-ALL. The functional impact of this mutation, which is unlikely to be gain-of-function, was not evaluated as yet.
Entity name
Multiple sclerosis
Disease
A single nucleotide polymorphism at position 244(T/I) is associated with increased risk of mutiple sclerosis. T244 promotes increased exon 6 skipping leading to higher production of soluble IL7-Ra (Lundmark et al., 2007; Hafler et al., 2007). The role of the soluble form of the receptor in MS warrants investigation.
Entity name
Rheumatoid arthritis
Disease
The 244(T/I) polymorphism was also found to be associated with rheumatoid arthritis risk (ODoherty et al., 2009).
Entity name
Omenn syndrome (OS)
Disease
A patient with OS, a SCID syndrome with graft-vesus-host disease symptoms, was found to have a mutation (C118Y) in the IL-7R (Giliani et al., 2006). This mutation was previously found correlated with SCID (Giliani et al., 2005).
Entity name
Allogeneic stem cell transplantation (SCT)
Note
The single nucleotide polymorphism (SNPs) IL7Ra +1237 A/G (position) in the donors for SCT was found to correlate with survival of the recipient after SCT (Shamim et al., 2006).
Entity name
HIV infection
Disease
Although the effects of IL-7/IL-7R during HIV infection on T-cells are well established, they are complex and still under heavy investigation. This entry only superficially covers some aspects of this relationship.
During HIV infection, T-cells have decreased IL-7R expression compared to healthy controls as well as decreased responsiveness to IL-7 (Carini et al., 1994; Vingerhoets et al., 1998).
The HIV Tat protein was found to be responsible for the downregulation of the receptor in CD8 T-cells (Faller et al., 2006).
The soluble IL-7R is increased in HIV+ individuals and can decrease the IL-7 activity in CD8 T-cells (Crawley et al., 2010).
Administration of IL-7 to HIV+ individuals under anti-retroviral therapy leads to an expansion of the T-cell compartment (Sereti et al., 2009; Levy et al., 2009) which may help to restore normal T-cell levels, however increased persistence of the virus in the affected individuals during therapy (Vandergeeten et al., 2013) may raise some concerns regarding the IL-7 therapy.
Comprehensive reviews on this topic include, but are not restricted to: Crawley and Angel, 2012; Sieg, 2012.

Bibliography

Pubmed IDLast YearTitleAuthors
149627142004Aberrant expression of interleukin-7 (IL-7) and its signalling complex in human breast cancer.Al-Rawi MA et al
155903962004Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia.Barata JT et al
153535582004Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells.Barata JT et al
78057181994Dysregulation of interleukin-7 receptor may generate loss of cytotoxic T cell response in human immunodeficiency virus type 1 infection.Carini C et al
204598612010Gene-based outcome prediction in multiple cohorts of pediatric T-cell acute lymphoblastic leukemia: a Children's Oncology Group study.Cleaver AL et al
118589392002Interleukin-7 receptor expression and activation in nonhaematopoietic neoplastic cell lines.Cosenza L et al
224215742012The influence of HIV on CD127 expression and its potential implications for IL-7 therapy.Crawley AM et al
83972271993Activation of phosphatidylinositol-3 kinase by ligation of the interleukin-7 receptor on human thymocytes.Dadi HK et al
16502611991Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells.Dibirdik I et al
18598881991Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias.Digel W et al
169670442006Interleukin-7 receptor expression on CD8 T-cells is downregulated by the HIV Tat protein.Faller EM et al
116725352001Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway.Fleming HE et al
81138391994Costimulation of cutaneous T-cell lymphoma cells by interleukin-7 and interleukin-2: potential autocrine or paracrine effectors in the Sézary syndrome.Foss FM et al
84592231993Genes for interleukin 7 are transcribed in leukemic cell subsets of individuals with chronic lymphocytic leukemia.Frishman J et al
164924422006Omenn syndrome in an infant with IL7RA gene mutation.Giliani S et al
156610252005Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients.Giliani S et al
23178651990Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily.Goodwin RG et al
222700702012TSLP and immune homeostasis.Hanabuchi S et al
201901942010IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Ralpha in T cells.Henriques CM et al
176605302007Risk alleles for multiple sclerosis identified by a genomewide study.Hafler DA et al
156152572004Characterization of a novel nonsense mutation in the interleukin-7 receptor alpha gene in a Korean patient with severe combined immunodeficiency.Jo EK et al
108914652000Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia.Karawajew L et al
230692542013Somatic mutation of IL7R exon 6 in acute leukemias and solid cancers.Kim MS et al
110528102000Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all.Korte A et al
179849842008Murine thymic stromal lymphopoietin promotes the differentiation of regulatory T cells from thymic CD4(+)CD8(-)CD25(-) naïve cells in a dendritic cell-independent manner.Lee JY et al
192870902009Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment.Levy Y et al
77199381995The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.Lin JX et al
176403762007Evolution of Class I cytokine receptors.Liongue C et al
176608162007Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.Lundmark F et al
90424311997Interleukin-7 (IL-7) in colorectal cancer: IL-7 is produced by tissues from colorectal cancer and promotes preferential expansion of tumour infiltrating lymphocytes.Maeurer MJ et al
185664152008MEK1/2 induces STAT5-mediated germline transcription of the TCRgamma locus in response to IL-7R signaling.Maki K et al
172599702007Interleukin-7 receptor expression: intelligent design.Mazzucchelli R et al
197441462009IL7RA polymorphisms and chronic inflammatory arthropathies.O'Doherty C et al
85903021995Cytokine mRNA expression patterns in human esophageal cancer cell lines.Oka M et al
201189292010Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells.Park JH et al
228593012012Synergistic effects of interleukin-7 and pre-T cell receptor signaling in human T cell development.Patel ES et al
98432161998Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency.Puel A et al
117395042001IL-7 enhances the survival and maintains the size of naive T cells.Rathmell JC et al
232348702013IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia.Ribeiro D et al
110235142000A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency.Roifman CM et al
194942612009Identification and biochemical characterization of human plasma soluble IL-7R: lower concentrations in HIV-1-infected patients.Rose T et al
93984041997IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.Rosenthal LA et al
200607402010IL-7 receptor is expressed on adult pre-B-cell acute lymphoblastic leukemia and other B-cell derived neoplasms and correlates with expression of proliferation and survival markers.Sasson SC et al
193808682009IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection.Sereti I et al
164350142006Genetic polymorphisms in the genes encoding human interleukin-7 receptor-alpha: prognostic significance in allogeneic stem cell transplantation.Shamim Z et al
215367382011Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias.Shochat C et al
225913582012Interleukin-7 biology in HIV disease and the path to immune reconstitution.Sieg SF et al
215931922011IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias.Silva A et al
220870332011The long-term survival potential of mature T lymphocytes is programmed during development in the thymus.Sinclair C et al
98340711998IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire.Soares MV et al
232699872013Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence.Suzuki K et al
21895051990Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia.Touw I et al
98630051999Constitutive and IFN-gamma regulated expression of IL-7 and IL-15 in human renal cell cancer.Trinder P et al
235896722013Interleukin-7 promotes HIV persistence during antiretroviral therapy.Vandergeeten C et al
75221651994Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the alpha chain of the interleukin-7 receptor.Venkitaraman AR et al
95623751998Altered receptor expression and decreased sensitivity of T-cells to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV infection.Vingerhoets J et al
161211852005Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus.Watanabe N et al
117283422001The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.Ye SK et al
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Other Information

Locus ID:

NCBI: 3575
MIM: 146661
HGNC: 6024
Ensembl: ENSG00000168685

Variants:

dbSNP: 3575
ClinVar: 3575
TCGA: ENSG00000168685
COSMIC: IL7R

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000168685ENST00000303115P16871
ENSG00000168685ENST00000505093H0YA41
ENSG00000168685ENST00000506850P16871
ENSG00000168685ENST00000508941D6RG28
ENSG00000168685ENST00000511982D6RDM4
ENSG00000168685ENST00000514217B8YG18
ENSG00000168685ENST00000515665D6RCR9

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Jak-STAT signaling pathwayKEGGko04630
Hematopoietic cell lineageKEGGko04640
Primary immunodeficiencyKEGGko05340
Cytokine-cytokine receptor interactionKEGGhsa04060
Jak-STAT signaling pathwayKEGGhsa04630
Hematopoietic cell lineageKEGGhsa04640
Primary immunodeficiencyKEGGhsa05340
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
FoxO signaling pathwayKEGGhsa04068
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-7 signalingREACTOMER-HSA-1266695

References

Pubmed IDYearTitleCitations
168186782006CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.795
176605302007Risk alleles for multiple sclerosis identified by a genomewide study.549
176605302007Risk alleles for multiple sclerosis identified by a genomewide study.549
168186762006Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells.461
176608172007Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.192
176608172007Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.192
195259552009Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20.185
176608162007Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.142
218921592011Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia.130
215367382011Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias.115

Citation

Daniel Ribeiro ; João T Barata

IL7R (interleukin 7 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/51090/il7r