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, apleiotropiccytokine which plays an important role in immunehomeostasis.[5][6]
The humanprotein interleukin-2 receptor subunit alpha is encoded by agene calledIL2RA with a length around 51,6 kb. Alternative names for this protein coding gene areIL2R,IDDM10 andTCGFR. Location ofIL2RA in humangenome is 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 toIL2RA gene 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]
IL2RA geneorthologues with identical protein functionality are relatively abundant and constant among animal species, especially inmammals subgroups. Moreover, conserved homologs of this gene are in mouse, rat, dog, cow, chimpanzee and Rhesus monkey.[15][16]
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 somemyeloid lineage cells (e.g.macrophages,dendritic cells).[17][18]IL2RA has been used as a marker to identify CD4+FoxP3+regulatory T cells in mice. However, there are species differences as CD25 is constitutively expressed by a large proportion of restingmemory T cells non-regulatory CD4 T cells in humans that are absent in mice.[19][20] High expression of CD25 is also found onTCR activated 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]
IL2RA protein can be expressed in many types ofneoplastic cells, such as in most B-cell neoplasms, T-celllymphomas, some acute nonlymphocyticleukemias,neuroblastomas,mastocytosis,Waldenstrom macroglobuliaemia andtumor infiltrating lymphocytes.[22][23]
Interleukin-2 receptor alpha chain is anintegral-membrane protein, more preciselytype I transmembrane protein. This bitopic polypeptide is constructed by a sequence of 272amino acids and 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 site forinterleukin-2, short cytoplasmic domain lacks an ability to induceintracellular signalling and 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-15 andIL-21), and the CD122 subunit binds alsoIL-15.[5][24][25]
SolubleIL2RA has been isolated and determined to result from extracellularproteolysis during activation of T lymphocytes.[18] Also, alternately-splicedIL2RAmRNAs have been isolated, but the significance of each is currently unknown.[26]
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 the addition of an alpha subunit (CD25) constructs the IL-2 receptor and provides enhanced specific binding force. After activation of the receptor by itsligand,heterodimerisation of beta and gamma intracellular domains takes place.[5][24] This coupling of subunits brings togetherJanus kinasesJAK1 andJAK3, considering their association with respective cytoplasmic parts of beta and gamma subunits.
Downstreamphosphorylation leads to initiation of three signalling pathways:JAK-STAT pathway,PI3K/Akt/mTOR pathway andRas/Raf/MEK/ERK (MAPK) pathway. Regarding JAK-STAT pathway, particularsignal transducers and activators of transcription participate in this signalling cascade, namelySTAT5,STAT1 andSTAT3. Afterdimerisation, they translocate to nucleus to performtranscription factor functions. All three signalling pathways are important for diverse cellular regulations, in terms of increased survival (anti-apoptotic effect), proliferation andcell growth, transcriptional regulation andcell differentiation.[25][6]
T lymphocytes are influenced by IL-2R signalling in case ofCD4+ T helper subtype 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 lymphocytes may be connected to phenotypic fate of these cells for effector and memory T cells formation.[5][18][27]
Roifman's group was the first to identify immunological consequences of CD25 loss and the patient has suffered fromchronic infections and severeautoimmunity resembling Immune dysregulation,Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome, caused by mutations inFOXP3 gene.[24]
Levels of CD25 soluble form, calledsIL-2Rα, has been connected to pathogenesis ofautoimmune diseases andcancer. Since sCD25 is produced during immune activation, it is used as one ofbiomarkers to 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 forleukemia andlymphoma.[29] Furthermore,sIL-2Rα levels have some significance also ininfectious diseases andtransplantation. Higher serum levels were correlated with severity and need for hospitalisation ofCOVID-19 patients.[30]sIL-2Rα amount 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-2Rα andautoantibodies.[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-2Rα has positive correlation withhypertension,type 2 diabetes mellitus,cardiac sarcoidosis,stroke andheart failure. For neurological disorders, high levels ofsIL-2Rα are a sign for increased risk of developingschizophrenia.[18]
SinceTregs expressIL-2Rα subunit constitutively on the surface, some immunotherapeutic approaches try to use this information for selectivity.[28] NARA1antibody is used in antitumour approaches to preferentially supplement interleukin-2 to conventionalCD8+ T cells . NARA1 binds to the cytokine on theIL-2Rαbinding site preventing binding to CD25. This complex should therefore interact with conventional T lymphocytes over T regulatory cells and thus increasecytotoxic activity without increasing suppressing activity in tumour environment.[32] Antibodies directly against CD25 have been altered to contain ‘activating’Fc regions for the purpose ofantibody-dependent cell-mediated cytotoxicity, in this case Treg depletion. Antibody marks a cell withIL-2Rα subunit on the surface, which is subsequently recognized and cleared bymyeloid cell withFc receptor.[5] Moreover, for treatment ofmultiple sclerosis, drug calleddaclizumab binds toIL2RA and so blocks high-affinity IL-2 receptors on recently activated T cells for interaction with IL-2 as well as IL-2cross-presentation bydendritic cells.[33][34]
From the other side, treatment strategies forautoimmune andinflammatory diseases need selectivity forTregs and suppression of immune system.IL-2Rα subunit 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 C virus-inducedvasculitis andsystemic lupus.[5][6]
