Wikipedia

IL2RA

(Redirected fromCD25)

"CD25" redirects here. Not to be confused withCdc25.

Theinterleukin-2 receptor alpha chain(also called Tac antigen, P55, and mainlyCD25) is a protein involved in the assembly of the high-affinityinterleukin-2 receptor,consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts withinterleukin-2,apleiotropiccytokinewhich plays an important role in immunehomeostasis.[5][6]

IL2RA
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesIL2RA,CD25, IDDM10, IL2R, TCGFR, p55, IMD41, interleukin 2 receptor subunit alpha
External IDsOMIM:147730;MGI:96549;HomoloGene:360;GeneCards:IL2RA;OMA:IL2RA - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3559

16184

Ensembl

ENSG00000134460

ENSMUSG00000026770

UniProt

P01589

P01590

RefSeq (mRNA)

NM_000417
NM_001308242
NM_001308243

NM_008367

RefSeq (protein)

NP_000408
NP_001295171
NP_001295172

NP_032393

Location (UCSC)Chr 10: 6.01 – 6.06 MbChr 2: 11.65 – 11.7 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Genetics

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The humanproteininterleukin-2 receptor subunit alpha is encoded by agenecalledIL2RAwith a length around 51,6 kb. Alternative names for this protein coding gene areIL2R,IDDM10andTCGFR.Location ofIL2RAin humangenomeis on the short arm of 10th chromosome (10p15.1).[7][8][9]

Several frequent pointmutations,single nucleotide polymorphism(SNP), have been identified in or in close proximity toIL2RAgene in the population. These SNPs have been linked mainly to susceptibility to immune dysregulation disorders, with majority found in research onmultiple sclerosis(MS) andtype 1 diabetes mellitus.[10][11][12][13][14]

IL2RAgeneorthologueswith identical protein functionality are relatively abundant and constant among animal species, especially inmammalssubgroups. Moreover, conserved homologs of this gene are in mouse, rat, dog, cow, chimpanzee and Rhesus monkey.[15][16]

Expression

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CD25 is expressed broadly amongleukocytes.The highest surface expression of this protein is onregulatory T cells (Tregs),where CD25 is expressed constitutively, especially on a subset classified as naturally occurring Tregs. It can also be found on activatedB cells,NK (natural killer) cells,thymocytes,and somemyeloidlineage cells (e.g.macrophages,dendritic cells).[17][18]IL2RAhas been used as a marker to identify CD4+FoxP3+regulatory T cellsin mice. However, there are species differences as CD25 is constitutively expressed by a large proportion of restingmemory T cellsnon-regulatory CD4 T cells in humans that are absent in mice.[19][20]High expression of CD25 is also found onTCRactivated conventional T cells (bothCD8+andCD4+T lymphocytes), where it is considered to be a marker of T cell activation.[21]Additionally, expression of the IL-2 receptor alpha subunit can be found in non-lymphoid tissues such as lungs (alveolar macrophages), liver (Kupffer cells) and skin (Langerhans cells).[5][18]

IL2RAprotein can be expressed in many types ofneoplastic cells,such as in most B-cell neoplasms, T-celllymphomas,some acute nonlymphocyticleukemias,neuroblastomas,mastocytosis,Waldenstrom macroglobuliaemiaandtumor infiltrating lymphocytes.[22][23]

Structure

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Interleukin-2 receptor alpha chain is anintegral-membrane protein,more preciselytype I transmembrane protein.This bitopic polypeptide is constructed by a sequence of 272amino acidsand has a molecular mass of around 30.8 kDa.[8]CD25 consists of three domains: extracellular (N-terminus), transmembrane (alpha-helix) and cytoplasmic (C-terminus). However, while extracellular part is able to function as abinding siteforinterleukin-2,short cytoplasmic domain lacks an ability to induceintracellular signallingand therefore needs to oligomerise with other IL-2 receptor subunits.[8][9]Theinterleukin-2(IL2) receptor alpha (IL2RA) and beta (IL2RB)chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL-2 receptor complex (Kd ~10−11M). Homodimeric alpha chains (IL2RA) result in low-affinity receptor (Kd ~10−8M) with no signalling ability, while dimeric beta (IL2RB) and gamma chains (IL2RG) produce a medium-affinity receptor (Kd ~10−9M). Moreover, CD25 is an exclusive subunit that entirely binds IL-2, while CD132 binds the shared γc family cytokines (IL-4,IL-7,IL-9,IL-15andIL-21), and the CD122 subunit binds alsoIL-15.[5][24][25]

SolubleIL2RAhas been isolated and determined to result from extracellularproteolysisduring activation of T lymphocytes.[18]Also, alternately-splicedIL2RAmRNAshave been isolated, but the significance of each is currently unknown.[26]

Signalling cascade of interleukin-2 Receptor

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Interleukin-2 can interact with intermediate-affinity dimeric IL-2 receptor, which consists of beta (CD122) and gamma (CD132) chains or with high-affinity trimeric complex, where also alpha subunit (CD25) constructs the IL-2 receptor and provides enhanced specific binding force. After activation of the receptor by itsligand,heterodimerisationof beta and gamma intracellular domains takes place.[5][24]This coupling of subunits brings togetherJanus kinasesJAK1andJAK3,considering their association with respective cytoplasmic parts of beta and gamma subunits. Downstreamphosphorylationleads to initiation of three signalling pathways:JAK-STAT pathway,PI3K/Akt/mTOR pathwayandRas/Raf/MEK/ERK (MAPK) pathway.Regarding JAK-STAT pathway, particularsignal transducers and activators of transcriptionparticipate in this signalling cascade:STAT5,STAT1andSTAT3and afterdimerisation,they translocate to nucleus to performtranscription factorfunctions. All three signalling pathways are important for diverse cellular regulations, in terms of increased survival (anti-apoptoticeffect), proliferation andcell growth,transcriptional regulation andcell differentiation.[25][6]T lymphocytes are influenced by IL-2R signalling in case ofCD4+ T helpersubtype differentiation: promotingTh1,Th2,Th9,Tfr (T follicular regulatory cells) and suppressingTh17,Tfh ( T follicular helper cells). Additionally, strength of IL-2R signalling inCD8+ T cytotoxic lymphocytesmay be connected to phenotypic fate of these cells for effector and memory T cells formation.[5][18][27]

Clinical significance

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Roifman's group was the first to identify immunological consequences of CD25 loss and the patient has suffered fromchronic infectionsand severeautoimmunityresembling Immune dysregulation,Polyendocrinopathy,Enteropathy, X-linked (IPEX) syndrome, caused by mutations inFOXP3gene.[24]

CD25 as a biomarker

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Levels of CD25 soluble form, calledsIL-2Rα,has been connected to pathogenesis ofautoimmune diseasesandcancer.Since sCD25 is produced during immune activation, it is used as one ofbiomarkersto track disease progression and to indicate outcome for clinical disorders. Especially, it is a hallmark for hyper-activated immune system andcytokine storm,which may lead to multiple organ system failure.[28]In cancer, increased levels of this soluble protein are diagnostic marker forleukemiaandlymphoma.[29]Furthermore,sIL-2Rαlevels have some significance also ininfectious diseasesandtransplantation.Higher serum levels were correlated with severity and need for hospitalisation ofCOVID-19patients.[30]sIL-2Rαamount in plasma ofHIV ( human immunodeficiency virus)positive patients has a correlation to HIV viral load and so to disease progression. Similarly inChagas disease,caused by theprotozoanTrypanosoma cruzi,patients have increased levels ofsIL-2Rαandautoantibodies.[31]In regard totransplantation,higher levels of sCD25 may be used as a predictor of organ rejection andgraft-versus-host disease (GVHD)forhematopoietic transplantations.ConcerningCVD (cardiovascular diseases)solubleIL-2Rαhas positive correlation withhypertension,type 2 diabetes mellitus,cardiac sarcoidosis,strokeandheart failure.For neurological disorders, high levels ofsIL-2Rαare a sign for increased risk of developingschizophrenia.[18]

CD25 as a therapeutic target

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SinceTregsexpressIL-2Rαsubunit constitutively on the surface, some immunotherapeutic approaches try to use this information for selectivity.[28]NARA1antibodyis used in antitumour approaches to preferentially supplement interleukin-2 to conventionalCD8+ T cells.NARA1 binds to the cytokine on theIL-2Rαbinding sitepreventing binding to CD25. This complex should therefore interact with conventional T lymphocytes over T regulatory cells and thus increasecytotoxicactivity without increasing suppressing activity in tumour environment.[32]Antibodies directly against CD25 have been altered to contain ‘activating’Fc regionsfor the purpose ofantibody-dependent cell-mediated cytotoxicity,in this case Treg depletion. Antibody marks a cell withIL-2Rαsubunit on the surface, which is subsequently recognized and cleared bymyeloid cellwithFc receptor.[5]Moreover, for treatment ofmultiple sclerosis,drug calleddaclizumabbinds toIL2RAand so blocks high-affinity IL-2 receptors on recently activated T cells for interaction with IL-2 as well as IL-2cross-presentationbydendritic cells.[33][34]

From the other side, treatment strategies forautoimmuneandinflammatorydiseases need selectivity forTregsand suppression of immune system.IL-2Rαsubunit expression on Tregs secures better sensitivity toIL-2.Therefore, administration of low doses of the cytokine preferentially stimulates T regulatory cells over others. Low-dose IL-2 therapy is used forgraft-versus-host disease,type 1 diabetes mellitus,hepatitis Cvirus-inducedvasculitisandsystemic lupus.[5][6]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000134460–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000026770–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcdefgSpolski R, Li P, Leonard WJ (October 2018). "Biology and regulation of IL-2: from molecular mechanisms to human therapy".Nature Reviews. Immunology.18(10): 648–659.doi:10.1038/s41577-018-0046-y.PMID30089912.S2CID51939991.
  6. ^abcZhou P (October 2022). "Emerging mechanisms and applications of low-dose IL-2 therapy in autoimmunity".Cytokine & Growth Factor Reviews.67:80–88.doi:10.1016/j.cytogfr.2022.06.003.PMID35803833.S2CID250200065.
  7. ^Leonard WJ, Donlon TA, Lebo RV, Greene WC (June 1985). "Localization of the gene encoding the human interleukin-2 receptor on chromosome 10".Science.228(4707): 1547–1549.Bibcode:1985Sci...228.1547L.doi:10.1126/science.3925551.PMID3925551.
  8. ^abc"IL2RA Gene - GeneCards | IL2RA Protein | IL2RA Antibody".www.genecards.org.Retrieved2023-01-25.
  9. ^ab"UniProt".www.uniprot.org.Retrieved2023-01-25.
  10. ^Buhelt S, Søndergaard HB, Oturai A, Ullum H, von Essen MR, Sellebjerg F (June 2019)."Relationship between Multiple Sclerosis-AssociatedIL2RARisk Allele Variants and Circulating T Cell Phenotypes in Healthy Genotype-Selected Controls ".Cells.8(6): 634.doi:10.3390/cells8060634.PMC6628508.PMID31242590.
  11. ^Pourakbari R, Hosseini M, Aslani S, Ayoubi-joshaghani MH, Valizadeh H, Roshangar L, et al. (September 2020). "Association between interleukin 2 receptor A gene polymorphisms (rs2104286 and rs12722489) with susceptibility to multiple sclerosis in Iranian population".Meta Gene.25:100750.doi:10.1016/j.mgene.2020.100750.
  12. ^Qu HQ, Montpetit A, Ge B, Hudson TJ, Polychronakos C (April 2007)."Toward further mapping of the association between the IL2RA locus and type 1 diabetes".Diabetes.56(4): 1174–1176.doi:10.2337/db06-1555.PMID17395754.
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  14. ^Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, et al. (September 2007). "Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes".Nature Genetics.39(9): 1074–1082.doi:10.1038/ng2102.PMID17676041.S2CID13940200.
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  18. ^abcdeLi Y, Li X, Geng X, Zhao H (October 2022). "The IL-2A receptor pathway and its role in lymphocyte differentiation and function".Cytokine & Growth Factor Reviews.67:66–79.doi:10.1016/j.cytogfr.2022.06.004.PMID35803834.S2CID250252097.
  19. ^Triplett TA, Curti BD, Bonafede PR, Miller WL, Walker EB, Weinberg AD (July 2012). "Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG".European Journal of Immunology.42(7): 1893–1905.doi:10.1002/eji.201242444.PMID22585674.
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  28. ^abDamoiseaux J (September 2020)."The IL-2 - IL-2 receptor pathway in health and disease: The role of the soluble IL-2 receptor".Clinical Immunology.218:108515.doi:10.1016/j.clim.2020.108515.PMID32619646.
  29. ^Janik JE, Morris JC, Pittaluga S, McDonald K, Raffeld M, Jaffe ES, et al. (November 2004)."Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma".Blood.104(10): 3355–3357.doi:10.1182/blood-2003-11-3922.PMID15205267.
  30. ^Kaya H, Kaji M, Usuda D (April 2021)."Soluble interleukin-2 receptor levels on admission associated with mortality in coronavirus disease 2019".International Journal of Infectious Diseases.105:522–524.doi:10.1016/j.ijid.2021.03.011.PMC7942057.PMID33711520.
  31. ^Mengel J, Cardillo F, Pontes-de-Carvalho L (2016-05-13)."Chronic Chagas' Disease: Targeting the Interleukin-2 Axis and Regulatory T Cells in a Condition for Which There Is No Treatment".Frontiers in Microbiology.7:675.doi:10.3389/fmicb.2016.00675.PMC4866556.PMID27242702.
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Further reading

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