IKZF2

Last updated
IKZF2
Identifiers
Aliases IKZF2 , ANF1A2, HELIOS, ZNF1A2, ZNFN1A2, IKAROS family zinc finger 2
External IDs OMIM: 606234 MGI: 1342541 HomoloGene: 22659 GeneCards: IKZF2
Orthologs
SpeciesHumanMouse
Entrez

22807

22779

Ensembl

ENSG00000030419

ENSMUSG00000025997

UniProt

Q9UKS7

P81183

RefSeq (mRNA)

NM_011770

RefSeq (protein)
Location (UCSC) Chr 2: 213 – 213.15 Mb Chr 1: 69.57 – 69.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Zinc finger protein Helios is a protein that in humans is encoded by the IKZF2 gene. [5] [6] [7] This protein is a member of Ikaros family of transcription factors. [8]

Contents

This gene 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 with Ikaros being expressed in all hematopoietic cells. [8] This protein forms homo- or hetero-dimers with other Ikaros family members. Multiple transcript variants encoding different isoforms have been found for this gene, 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 one transcription factor is defected, others can substitute it. Because of this, it is rather difficult to assess precise function to each transcription factor. [9]

Structure

Ikaros family members are characterised by having 4 N-terminal zinc 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 have C-terminal zinc finger domains which serve as a site for interactions with other proteins and hetero- or homodimerization with other family members. [9]

Function

As transcription factor

Helios is said to repress the IL-2 expression in Tregs. This function was also confirmed for Eos, another member of Ikaros family of transcription factors, pointing to their redundant functions. Helios interacts with Foxp3 to lower IL2 expression. They form a complex and bind to the IL2 locus causing repressive epigenetic modifications, namely reduced histone H3 acetylation. [10] Loss of Helios causes decreased binding of Foxp3 to the IL2 promoter and milder IL-2 repression. [9]

Helios is also said to be part of the positive feedback loop of IL-2. It positively affects the IL-2Rα-STAT5 pathway. [11] [12] IL-2 maintains Helios expression. IL-2 is probably not the only factor positively affecting Helios expression. [11]

As a tumor suppressor

Helios is said to also function as a tumor suppressor. Such role of Helios was observed when a dominant negative isoform of this protein, that lacked three out of four N-terminal zinc fingers, was found in adult T cell malignancies. Indeed, forced expression of this isoform of Helios did lead to the development of T cell lymphoma in a murine model. However, the ectopic expression of wildtype Helios in B cells results in lymphomas as well. This suggests that Helios might act as a tumor suppressor only in the cells that it is naturally expressed in, when expressed in other cells, it is rather tumorigenic. [8]

Since Helios-deficient Tregs have the ability to produce IFN-γ and TNF-α, they seem to be useful in anti-tumor responses. Such Treg cells can infiltrate the tumor without keeping their suppressive function, subsequently producing IFN-γ and TNF-α, which could help with slowing the tumor growth. Moreover, the loss of suppressive phenotype of Treg cells was observed in tumors, but not in splenic Tregs, 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]

In immune cells

Helios is expressed in many mature T lymphocyte populations, however, it is best known for its expression in T regulatory cell (Treg) population. [9]

Tregs

Treg cells are a population of T cells that can suppress the effector function of other immune cells. [13] We can divide Treg cells into two main subsets: thymus-derived Treg cell (tTreg) and peripherally-induced Treg cell (pTreg). TTregs are the subset of cells that develops in thymus from T lymphocytes that recognise self-antigens. Whereas pTregs are lymphocytes that are induced in the periphery originally from CD4+ Foxp3- cells and which subsequently acquire suppressive function. Both Treg cells subsets are Foxp3+. [8]

Helios is expressed only in 70-80 % of Treg cells in mice and humans. The fact that Helios is not expressed in all Tregs 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 early Foxp3+ thymocytes or that did not find the expression of Helios in Tregs 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 Helios transcription 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 of Treg stability rather than a specific marker for differentiation between tTregs and pTregs. [11]

It was discovered that Helios is not essential for early development of T cells in thymus, but it is important for Treg suppressive function later in their life. This conclusion was drawn when the loss of Helios in T cells did not have any effect on T cell development and homeostasis of the immune system in a mouse model. However, it did result in a defective immune regulation later in the life with the onset of autoimmunity resulting from defective Treg function. [11]

Tregs that lack Helios have lower expression of Foxp3 and lower activation of STAT5. Helios-deficient Tregs also seem to produce effector cytokines that are not usually produced by this cell type – interleukin 17 (IL-17), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). [10] Thus, this suggests that Helios is important for the identity of Treg cell and stability of their cytokine profile. It is important to mention, that so far we do not have enough knowledge about the mechanism of Helios keeping Treg stability and even about Helios's own expression in Tregs. Thus, there is a need to uncover the mechanism behind these findings. [11]

In other immune cells

Beside CD4+ Tregs, Helios is also expressed in murine NK cells. In this immune cell subset, Helios is expressed early during their development, and it is later downregulated. [8]

Helios is also expressed in CD8+ regulatory T cells. Helios maintains their suppressive function similarly to the CD4+ Tregs. [12]

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

<span class="mw-page-title-main">IPEX syndrome</span> Medical condition

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is a rare autoimmune disease. It is one of the autoimmune polyendocrine syndromes. Most often, IPEX presents with autoimmune enteropathy, dermatitis (eczema), and autoimmune endocrinopathy, but other presentations exist.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">CD83</span>

CD83 is a human protein encoded by the CD83 gene.

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

<span class="mw-page-title-main">IKZF1</span> Protein-coding gene in the species Homo sapiens

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.

<span class="mw-page-title-main">IKZF3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein Aiolos also known as Ikaros family zinc finger protein 3 is a protein that in humans is encoded by the IKZF3 gene.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">IL2RA</span> Mammalian protein found in Homo sapiens

The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.

<span class="mw-page-title-main">RNF128</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase RNF128 is an enzyme that in humans is encoded by the RNF128 gene.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Infectious tolerance is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural in vivo process. A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000030419 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025997 - 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. ↑ Hahm K, Cobb BS, McCarty AS, Brown KE, Klug CA, Lee R, et al. (March 1998). "Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin". Genes & Development. 12 (6): 782–796. doi:10.1101/gad.12.6.782. PMC   316626 . PMID   9512513.
  6. ↑ Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA (April 1998). "Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors". Current Biology. 8 (9): 508–515. Bibcode:1998CBio....8..508K. doi: 10.1016/S0960-9822(98)70202-7 . PMID   9560339.
  7. 1 2 "Entrez Gene: IKZF2 IKAROS family zinc finger 2 (Helios)".
  8. 1 2 3 4 5 6 7 Thornton AM, Shevach EM (November 2019). "Helios: still behind the clouds". Immunology. 158 (3): 161–170. doi:10.1111/imm.13115. PMC   6797934 . PMID   31517385.
  9. 1 2 3 4 Read KA, Jones DM, Freud AG, Oestreich KJ (March 2021). "Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function". Immunological Reviews. 300 (1): 82–99. doi:10.1111/imr.12936. PMC   8015388 . PMID   33331000.
  10. 1 2 Powell MD, Read KA, Sreekumar BK, Oestreich KJ (2019-06-06). "Ikaros Zinc Finger Transcription Factors: Regulators of Cytokine Signaling Pathways and CD4+ T Helper Cell Differentiation". Frontiers in Immunology. 10: 1299. doi: 10.3389/fimmu.2019.01299 . PMC   6563078 . PMID   31244845.
  11. 1 2 3 4 5 6 Chougnet C, Hildeman D (August 2016). "Helios-controller of Treg stability and function". Translational Cancer Research. 5 (Suppl 2): S338–S341. doi: 10.21037/tcr.2016.07.37 . PMC   6333417 . PMID   30656143.
  12. 1 2 Nakagawa H, Wang L, Cantor H, Kim HJ (2018-01-01). Alt F (ed.). New Insights into the Biology of CD8 Regulatory T Cells. Advances in Immunology. Vol. 140. Academic Press. pp. 1–20. doi:10.1016/bs.ai.2018.09.001. ISBN   978-0-12-815186-0. PMID   30366517.
  13. 1 2 Mohr A, Malhotra R, Mayer G, Gorochov G, Miyara M (2018). "Human FOXP3+ T regulatory cell heterogeneity". Clinical & Translational Immunology. 7 (1): e1005. doi:10.1002/cti2.1005. PMC   5822410 . PMID   29484183.

Further reading

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