The type III
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
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. They were discovered in 2003.
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.
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
Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 (alternative name IFNλ1) plays an important role in the immune response against pathogenes and especially against vi ...
, is located downstream of IFNL2, encoding
IL-28A. IFNL3, encoding
IL28B
Interferon lambda 3 (gene symbol: ''IFNL3)'' encodes the IFNL3 protein. ''IFNL3'' was formerly named ''IL28B'', but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly disc ...
, is located downstream of IFNL4.
In mice, the genes encoding for type III interferons are located on chromosome 7 and the family consist only of IFN-λ2 and IFN-λ3.
Structure
Interferons
All interferon groups belong to class II cytokine family which have a conserved structure that comprises six
α-helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
.
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%.
Lowest similarity is found between IFN-λ4 and IFN-λ3 - only around 30%.
Unlike type I interferon group, which consist of only one exon, type III interferons consist of multiple exons.
Receptor
The receptors for these cytokines are also structurally conserved. The receptors have two type III
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
domains in their extracellular domain. The interface of these two domains forms the cytokine binding site.
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).
In contrast to the ubiquitous expression of receptors for type I interferons,
IFNLR1 is largely restricted to tissues of epithelial origin.
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.
Signalling pathway
IFN-λ production is induced by pathogen sensing through
pattern recognition receptors (PRR), including
TLR,
Ku70
Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene.
Function
Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of ...
and
RIG-I-like. The main producer of IFN-λ are type 2 myeloid dendritic cells.
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.
Upon binding of the cytokine to the receptor,
JAK-STAT signalling pathway gets activated, specifically
JAK1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
and
TYK2
Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene.
Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...
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
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
,
IRF, ISRE,
Mx1,
OAS1
2'-5'-oligoadenylate synthetase 1 is an enzyme that in humans is encoded by the ''OAS1'' gene.
This gene encodes a member of the 2-5A synthetase family, which include essential proteins involved in the innate immune response to viral infection.
...
.
The signalling is modulated by
suppressor of cytokine signalling 1 (SOCS1) and ubiquitin-specific peptidase 18 (USP18).
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.
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. 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.
In the gastrointestinal tract, both type I and type III interferons are needed to effectively fight
reovirus
''Reoviridae'' is a family of double-stranded RNA viruses. Member viruses have a wide host range, including vertebrates, invertebrates, plants, protists and fungi. They lack lipid envelopes and package their segmented genome within multi-layered ...
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.
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.
References
{{Interferons
Cytokines
Antiviral drugs