Interferon type II

Interferon type II is a family of interferons involved in immune system regulation. There is only one member of type II interferons (IFNs), known as IFN-γ. IFN-γ is a cytokine which binds to the type II IFN receptor, or the IFN-γ receptor(IFNGR), to elicit a signal within its target cell. Through cell signaling, IFN-γ plays a role in regulating the immune response of its target cell.[1] A key signaling pathway that is activated by type II IFN is the JAK-STAT signaling pathway.[2] IFN-γ plays an important role in both innate and adaptive immunity. Type II IFN is primarily secreted by adaptive immune cells, more specifically CD4+ T helper 1 (Th1) cells, natural killer (NK) cells, and CD8+ cytotoxic T cells. The expression of type II IFN is upregulated and downregulated by cytokines.[3] By activating signaling pathways in cells such as macrophages, B cells, and CD8+ cytotoxic T cells, it is able to promote inflammation, antiviral or antibacterial activity, and cell proliferation and differentiation.[4] Type II IFN is serologically different from interferon type 1, binds to different receptors, and is encoded by a separate chromosomal locus.[5] Type II IFN has played a role in the development of cancer immunotherapy treatments due to its ability to prevent tumor growth.[3]

Not to be confused with Interferon type I.
Interferon type II (γ)
The three-dimensional structure of human interferon gamma (PDB: 1HIG​)
Identifiers
SymbolIFN-gamma
PfamPF00714
InterProIPR002069
CATH1d9cA00
SCOP2d1d9ca_ / SCOPe / SUPFAM

Production

The primary cells that secrete type II IFN are CD4+ T helper 1 (Th1) cells, natural killer (NK) cells, and CD8+ cytotoxic T cells. It can also be secreted by antigen presenting cells (APCs) such as dendritic cells (DCs), macrophages (MΦs), and B cells to a lesser degree. Type II IFN expression is upregulated by the production of interleukin cytokines, such as IL-12, IL-15, IL-18, as well as type I interferons (IFN-α and IFN-β).[3] Meanwhile, IL-4, IL-10, transforming growth factor-beta (TGF-β) and glucocorticoids are known to downregulate type II IFN expression.[4]

Function

Type II IFN is a cytokine, meaning it functions by signaling to other cells in the immune system and influencing their immune response. There are many immune cells type II IFN acts on. Some of its main functions are to induce IgG isotype switching in B cells; upregulate major histocompatibility complex (MHC) class II expression on APCs; induce CD8+ cytotoxic T cell differention, activation, and proliferation; and activate macrophages. In macrophages, type II IFN stimulates IL-12 expression. IL-12 in turn promotes the secretion of IFN-γ by NK cells and Th1 cells, and it signals naive T helper cells (Th0) to differentiate into Th1 cells.[1]

Signaling

IFN-γ binds to the type II cell-surface receptor, also known as the IFN-gamma receptor (IFNGR) which is part of the class II cytokine receptor family. The IFNGR is composed of two subunits: the IFNGR1 and IFNGR2. IFNGR1 is associated with JAK1 and IFNGR2 is associated with JAK2. Upon IFN-γ binding the receptor, IFNGR1 and IFNGR2 undergo conformational changes that result in the autophosphorylation and activation of JAK1 and JAK2. This leads to a signaling cascade and eventual transcription of target genes.[2] The expression of 236 different genes has been linked to type II IFN-mediated signaling. The proteins expressed by type II IFN-mediated signaling are primarily involved in promoting inflammatory immune responses and regulating other cell-mediated immune responses, such as apoptosis, intracellular IgG trafficking, cytokine signaling and production, hematopoiesis, and cell proliferation and differentiation.[4]

JAK-STAT pathway

One key pathway triggered by IFN-γ binding IFNGRs is the Janus Kinase and Signal Transducer and Activator of Transcription pathway, more commonly referred to as the JAK-STAT pathway. In the JAK-STAT pathway, activated JAK1 and JAK2 proteins regulate the phosphorylation of tyrosine in STAT1 transcription factors. The tyrosines are phosphorylated at a very specific location, allowing activated STAT1 proteins to interact with each other come together to form STAT1-STAT1 homodimers. The STAT1-STAT1 homodimers can then enter the cell nucleus. They then initiate transcription by binding to gamma interferon activation site (GAS) elements,[2] which are located in the promoter region of interferon-γ stimulated genes (ISGs) that express for antiviral effector proteins, as well as positive and negative regulators of type II IFN signaling pathways.[6]

JAK-STAT signaling pathway activated by type II IFN.

The JAK proteins also lead to the activation of phosphatidylinositol 3-kinase (PI3K). PI3K leads to the activation of protein kinase C-δ (PKC-δ) which phosphorylates the amino acid serine in STAT1 transcription factors. The phosphorylation of the serine in STAT1-STAT1 homodimers are essential for the full transcription process to occur.[2]

Other signaling pathways

Other signaling pathways that are triggered by IFN-γ are the mTOR signaling pathway, the MAPK signaling pathway, and the PI3K/AKT signaling pathway.[4]

Importance in cancer immunotherapy

The goal of cancer immunotherapy is to trigger an immune response by the patient's immune cells to attack and kill malignant (cancer-causing) tumor cells. Type II IFN deficiency has been linked to several types of cancer, including B-cell lymphoma and lung cancer. Furthermore, it has been found that in patients receiving the drug durvalumab to treat non-small cell lung carcinoma and transitional cell carcinoma had higher response rates to the drug, and the drug stunted the progression of both types of cancer for a longer duration of time. Thus, promoting the upregulation of type II IFN has been proven to be a crucial part in creating effective cancer immunotherapy treatments.[7]

Involvement in antitumor immunity

Type II IFN enhances Th1 cell, cytotoxic T cell, and APC activities, which results in an enhanced immune response against the malignant tumor cells, leading to tumor cell apoptosis and necroptosis (cell death). Furthermore, Type II IFN suppresses the activity of regulatory T cells, which are responsible for silencing immune responses against pathogens, preventing the deactivation of the immune cells involved in the killing of the tumor cells. Type II IFN prevents tumor cell division by directly acting on the tumor cells, which results in increased expression of proteins that inhibit the tumor cells from continuing through the cell cycle (i.e., cell cycle arrest). Type II IFN can also prevent tumor growth by indirectly acting on endothelial cells lining the blood vessels close to the site of the tumor, cutting off blood flow to the tumor cells and thus the supply of necessary resources for tumor cell survival and proliferation.[7]

Barriers

The importance of type II IFN in cancer immunotherapy has been acknowledged; current research is studying the effects of type II IFN on cancer, both as a solo form of treatment and as a form of treatment to be administered alongside other anticancer drugs. But type II IFN has not been approved by the Food and Drug Administration (FDA) to treat cancer, except for malignant osteoporosis. This is most likely due to the fact that while type II IFN is involved in antitumor immunity, some of its functions may enhance the progression of a cancer. When type II IFN acts on tumor cells, it may induce the expression of a transmembrane protein known as programmed death-ligand 1 (PDL1), which allows the tumor cells to evade an attack from immune cells. Type II IFN-mediated signaling may also promote angiogenesis (formation of new blood vessels to the tumor site) and tumor cell proliferation.[7]

See also

References
  1. Tau G, Rothman P (December 1999). "Biologic functions of the IFN-gamma receptors". Allergy. 54 (12): 1233–1251. doi:10.1034/j.1398-9995.1999.00099.x. PMC 4154595. PMID 10688427.
  2. Platanias LC (May 2005). "Mechanisms of type-I- and type-II-interferon-mediated signalling". Nature Reviews. Immunology. 5 (5): 375–386. doi:10.1038/nri1604. PMID 15864272. S2CID 1472195.
  3. Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ (2018). "Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion". Frontiers in Immunology. 9: 847. doi:10.3389/fimmu.2018.00847. PMC 5945880. PMID 29780381.
  4. Bhat MY, Solanki HS, Advani J, Khan AA, Keshava Prasad TS, Gowda H, et al. (December 2018). "Comprehensive network map of interferon gamma signaling". Journal of Cell Communication and Signaling. 12 (4): 745–751. doi:10.1007/s12079-018-0486-y. PMC 6235777. PMID 30191398.
  5. Lee AJ, Ashkar AA (2018). "The Dual Nature of Type I and Type II Interferons". Frontiers in Immunology. 9: 2061. doi:10.3389/fimmu.2018.02061. PMC 6141705. PMID 30254639.
  6. Schneider WM, Chevillotte MD, Rice CM (2014-03-21). "Interferon-stimulated genes: a complex web of host defenses". Annual Review of Immunology. 32 (1): 513–545. doi:10.1146/annurev-immunol-032713-120231. PMC 4313732. PMID 24555472.
  7. Ni L, Lu J (September 2018). "Interferon gamma in cancer immunotherapy". Cancer Medicine. 7 (9): 4509–4516. doi:10.1002/cam4.1700. PMC 6143921. PMID 30039553.
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