| IKZF2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | IKZF2, ANF1A2, HELIOS, ZNF1A2, ZNFN1A2, IKAROS family zinc finger 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:606234;MGI:1342541;HomoloGene:22659;GeneCards:IKZF2;OMA:IKZF2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Zinc finger protein Helios is aprotein that in humans is encoded by theIKZF2gene.[5][6][7] This protein is a member of Ikaros family of transcription factors.[8]
Thisgene encodes a member of the Ikaros family of zinc-finger proteins. This family of transcription factors consists of five members: Ikaros (Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5). The Ikaros family members are involved in the hematopoietic development, some to a greater extent than others withIkaros being expressed in all hematopoietic cells.[8] This protein forms homo- or hetero-dimers with other Ikaros family members. Multiple transcript variants encoding differentisoforms have been found for thisgene, but the biological relevance of some variants has not been determined.[7]
When these factors are missing or altered,lymphocytes suffer from defective development. Since Ikaros family members can interact with each other, it is probable that when onetranscription factor is defected, others can substitute it. Because of this, it is rather difficult to assess precise function to eachtranscription factor.[9]
Ikaros family members are characterised by having 4N-terminalzinc finger domains, except for Pegasus, which has only 3. These are the key domains for DNA binding and stabilization of DNA-protein interactions. They also haveC-terminalzinc finger domains which serve as a site for interactions with other proteins and hetero- or homodimerization with other family members.[9]
Helios is said to repress theIL-2 expression inTregs. This function was also confirmed forEos, another member of Ikaros family oftranscription factors, pointing to their redundant functions. Helios interacts withFoxp3 to lowerIL2 expression. They form a complex and bind to theIL2 locus causing repressive epigenetic modifications, namely reducedhistone H3acetylation.[10] Loss of Helios causes decreased binding ofFoxp3 to theIL2 promoter and milderIL-2 repression.[9]
Helios is also said to be part of thepositive feedback loop ofIL-2. It positively affects theIL-2Rα-STAT5 pathway.[11][12]IL-2 maintains Helios expression.IL-2 is probably not the only factor positively affecting Helios expression.[11]
Helios is said to also function as atumor suppressor. Such role of Helios was observed when a dominant negative isoform of this protein, that lacked three out of fourN-terminalzinc fingers, was found in adultT cellmalignancies. Indeed, forced expression of thisisoform of Helios did lead to the development ofT cell lymphoma in a murine model. However, the ectopic expression ofwildtype Helios inB cells results inlymphomas as well. This suggests that Helios might act as atumor suppressor only in the cells that it is naturally expressed in, when expressed in other cells, it is rather tumorigenic.[8]
Since Helios-deficientTregs have the ability to produceIFN-γ andTNF-α, they seem to be useful in anti-tumor responses. SuchTreg cells can infiltrate thetumor without keeping their suppressive function, subsequently producingIFN-γ andTNF-α, which could help with slowing thetumor growth. Moreover, the loss of suppressive phenotype ofTreg cells was observed intumors, but not in splenicTregs, which can potentially have great clinical significance. Based on these findings, Helios could be considered a powerful tool in the anti-tumor therapy. However, it is too early for such conclusion and even though the data seem promising, more research needs to be done in this area.[11]
Helios is expressed in many matureT lymphocyte populations, however, it is best known for its expression inT regulatory cell (Treg) population.[9]
Treg cells are a population ofT cells that can suppress the effector function of otherimmune cells.[13] We can divideTreg cells into two main subsets: thymus-derived Treg cell (tTreg) and peripherally-induced Treg cell (pTreg). TTregs are the subset of cells that develops inthymus fromT lymphocytes that recognise self-antigens. Whereas pTregs arelymphocytes that are induced in the periphery originally fromCD4+Foxp3- cells and which subsequently acquire suppressive function. BothTreg cells subsets areFoxp3+.[8]
Helios is expressed only in 70-80 % ofTreg cells in mice and humans. The fact that Helios is not expressed in allTregs was in the past explained by the observations that Helios could actually be found only in tTregs (Tregs that arise from the thymus), not pTregs. This believe was supported by experimental data, that discovered the expression of Helios only in earlyFoxp3+thymocytes or that did not find the expression of Helios inTregs in the periphery in the first few days. Moreover, experiments generating induced Tregs (iTregs)in vitro, did not find any expression of Helios in the cells. Thus, Helios used to be considered a tTreg marker.[8]
Recently, the idea of Helios as a tTregs specific marker, has become controversial. Current studies indicate that even iTregs can express Heliostranscription factor. Thus, it is unclear whether Helios can be used as a marker for tTregs.[8][13]
Current data suggest that Helios is a marker ofTreg stability rather than a specific marker for differentiation between tTregs and pTregs.[11]
It was discovered that Helios is not essential for early development ofT cells inthymus, but it is important forTreg suppressive function later in their life. This conclusion was drawn when the loss of Helios inT cells did not have any effect onT cell development andhomeostasis of theimmune system in a mouse model. However, it did result in a defective immune regulation later in the life with the onset ofautoimmunity resulting from defectiveTreg function.[11]
Tregs that lack Helios have lower expression ofFoxp3 and lower activation ofSTAT5. Helios-deficientTregs also seem to produce effectorcytokines that are not usually produced by this cell type –interleukin 17 (IL-17),interferon gamma (IFN-γ) andtumor necrosis factor alpha (TNF-α).[10] Thus, this suggests that Helios is important for the identity ofTreg cell and stability of theircytokine profile. It is important to mention, that so far we do not have enough knowledge about the mechanism of Helios keepingTreg stability and even about Helios's own expression inTregs. Thus, there is a need to uncover the mechanism behind these findings.[11]
BesideCD4+Tregs, Helios is also expressed in murineNK cells. In this immune cell subset, Helios is expressed early during their development, and it is later downregulated.[8]
Helios is also expressed inCD8+regulatory T cells. Helios maintains their suppressive function similarly to theCD4+Tregs.[12]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
