Biology:Interferon type III

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Short description: Group of anti-viral cytokines
Interferon type III (λ)
Identifiers
SymbolIL28A
PfamPF15177
InterProIPR029177
CATH3og6A00

The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3 (also known as IL29, IL28A and IL28B respectively), and IFN-λ4.[1] They were discovered in 2003.[2] Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.[3]

Genomic location

Genes encoding this group of interferons are all located on the long arm of chromosome 19 in human, specifically in region between 19q13.12 and 19q13.13. IFNL1 gene, encoding IL-29, is located downstream of IFNL2, encoding IL-28A. IFNL3, encoding IL28B, is located downstream of IFNL4.[4][5]

In mice, the genes encoding for type III interferons are located on chromosome 7 and the family consists only of IFN-λ2 and IFN-λ3.[6]

Type III interferon (interferon lambda) genes on human chromosome 19

Structure

Interferons

All interferon groups belong to class II cytokine family which have a conserved structure that comprises six α-helices.[7] The proteins of type III interferon group are highly homologous and show high amino acid sequence similarity between. The similarity between IFN-λ2 and IFN-λ3 is approximately 96%, similarity of IFNλ1 to IFNλ 2/3 is around 81%.[2] Lowest similarity is found between IFN-λ4 and IFN-λ3 - only around 30%.[8][9] Unlike type I interferon group, which consist of only one exon, type III interferons consist of multiple exons.[6][5]

Receptor

The receptors for these cytokines are also structurally conserved. The receptors have two type III fibronectin domains in their extracellular domain. The interface of these two domains forms the cytokine binding site.[7] The receptor complex for type III interferons consists of two subunits - IL10RB (also called IL10R2 or CRF2-4) and IFNLR1 (formerly called IL28RA, CRF2-12).[10]

In contrast to the ubiquitous expression of receptors for type I interferons, IFNLR1 is largely restricted to tissues of epithelial origin.[2][11][6] Despite high homology between type III interferons, the binding affinity to IFNLR1 differ, with IFN-λ1 showing the highest binding affinity, and IFN-λ3 showing the lowest binding affinity.[9]

Signalling pathway

IFN-λ production is induced by pathogen sensing through pattern recognition receptors (PRR), including TLR, Ku70 and RIG-I-like. The main producer of IFN-λ are type 2 myeloid dendritic cells.[5]

IFN-λ binds to IFNLR1 with a high affinity, which then recruits the low-affinity subunit of the receptor, IL10Rb. This interaction creates a signalling complex.[6] Upon binding of the cytokine to the receptor, JAK-STAT signalling pathway gets activated, specifically JAK1 and TYK2 and phosphorylate and activate STAT-1 and STAT-2, which then induces downstream signalling that leads to induction of expression of hundreds of IFN-stimulated genes (ISG), e.g.: NF-κB, IRF, ISRE, Mx1, OAS1.[5]

The signalling is modulated by suppressor of cytokine signalling 1 (SOCS1) and ubiquitin-specific peptidase 18 (USP18).[5]

Function

Functions of type III interferons overlap largely with that of type I interferons. Both of these cytokine groups modulate the immune response after a pathogen has been sensed in the organism, their functions are mostly anti-viral and anti-proliferative. However, type III interferons tend to be less inflammatory and show a slower kinetics than type I. Also, because of the restricted expression of IFNLR1, the immunomodulatory effect of type III interferons is limited.[6][12]

Because the receptors for type I and type II interferons are expressed on almost all nucleated cells, their function is rather systemic. Type III interferon receptors are expressed more specifically on epithelial cells and some immune cells such as neutrophils, and depending on the species, B cells and dendritic cells as well.[13][14][15] Therefore, their antiviral effects are most prominent in barriers, in gastrointestinal, respiratory and reproductive tracts. Type III interferons usually act as the first line of defense against viruses at the barriers.[3][16]

In the gastrointestinal tract, both type I and type III interferons are needed to effectively fight reovirus infection. Type III interferons restrict the initial replication of the virus and diminish the shedding of through feces, while type I interferons prevent the systematic infection. On the other hand, in the respiratory tract these two groups of interferons seem to be rather redundant, as documented by the susceptibility of double-deficient mice (in receptors for type I and type III interferons), but the resistance to respiratory virus in mice that are deficient in either type I or type III interferon receptors.[12] Additional gastrointestinal viruses such as rotavirus and norovirus, as well as non-gastrointestinal viruses like influenza and West Nile virus, are also restricted by type III interferons.[17]

References

  1. ↑ "Novel interferons". Nature Immunology 4 (1): 8–9. January 2003. doi:10.1038/ni0103-8. PMID 12496969. 
  2. ↑ 2.0 2.1 2.2 "IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology 4 (1): 69–77. January 2003. doi:10.1038/ni875. PMID 12483210. 
  3. ↑ 3.0 3.1 "Contribution of type III interferons to antiviral immunity: location, location, location". The Journal of Biological Chemistry 292 (18): 7295–7303. May 2017. doi:10.1074/jbc.R117.777102. PMID 28289095. 
  4. ↑ "Type III Interferons in Viral Infection and Antiviral Immunity" (in english). Cellular Physiology and Biochemistry 51 (1): 173–185. 2018. doi:10.1159/000495172. PMID 30439714. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Interferon Lambda: Modulating Immunity in Infectious Diseases". Frontiers in Immunology 8: 119. 2017-02-28. doi:10.3389/fimmu.2017.00119. PMID 28293236. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Shared and Distinct Functions of Type I and Type III Interferons". Immunity 50 (4): 907–923. April 2019. doi:10.1016/j.immuni.2019.03.025. PMID 30995506. 
  7. ↑ 7.0 7.1 "Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators". Nature Reviews. Immunology 3 (8): 667–76. August 2003. doi:10.1038/nri1153. PMID 12974481. 
  8. ↑ "IFN-λ4: the paradoxical new member of the interferon lambda family". Journal of Interferon & Cytokine Research 34 (11): 829–38. November 2014. doi:10.1089/jir.2013.0136. PMID 24786669. 
  9. ↑ 9.0 9.1 "The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family". PLOS ONE 4 (3): e4933. 2009-03-20. doi:10.1371/journal.pone.0004933. PMID 19300512. Bibcode: 2009PLoSO...4.4933F. 
  10. ↑ "Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model". The Journal of General Virology 86 (Pt 6): 1589–1596. June 2005. doi:10.1099/vir.0.80904-0. PMID 15914836. 
  11. ↑ "IL-28, IL-29 and their class II cytokine receptor IL-28R". Nature Immunology 4 (1): 63–8. January 2003. doi:10.1038/ni873. PMID 12469119. 
  12. ↑ 12.0 12.1 "Guarding the frontiers: the biology of type III interferons". Nature Immunology 16 (8): 802–9. August 2015. doi:10.1038/ni.3212. PMID 26194286. 
  13. ↑ Broggi, Achille; Tan, Yunhao; Granucci, Francesca; Zanoni, Ivan (October 2017). "IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function". Nature Immunology 18 (10): 1084–1093. doi:10.1038/ni.3821. ISSN 1529-2916. PMID 28846084. 
  14. ↑ "Interferon-λ modulates dendritic cells to facilitate T cell immunity during infection with influenza A virus". Nature Immunology 20 (8): 1035–1045. August 2019. doi:10.1038/s41590-019-0408-z. PMID 31235953. 
  15. ↑ "Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells". PLOS Pathogens 16 (4): e1008515. April 2020. doi:10.1371/journal.ppat.1008515. PMID 32353085. 
  16. ↑ "Interferon-λ: Immune Functions at Barrier Surfaces and Beyond". Immunity 43 (1): 15–28. July 2015. doi:10.1016/j.immuni.2015.07.001. PMID 26200010. 
  17. ↑ "Distinct Effects of Type I and III Interferons on Enteric Viruses". Viruses 10 (1): 46. January 2018. doi:10.3390/v10010046. PMID 29361691. 



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