The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections

Figures & data

Figure 1 (A) Sequence alignment of IFNLs. An amino-acid sequence alignment of human IFNL1–4 is shown. Red letters indicate significant differences. Green letters indicate common cysteines. Helices and exons are indicated with boxes. (B) Sequence alignment overlay for different IFNLs. Amino acids of significance are highlighted.

Figure 2 Expression dynamics of IFNs and ISGs during viral infection or inflammatory stimulation. Red line represents IFNL3, blue line IFN-α and black line IFNL4 expression dynamics. The lower panel illustrates the amount of ISG expression.

Table 1 Selection of important SNPs in the IFNL signaling cascade

Gene	SNP	Nucleotides	Localization	Impact on expression (minor allele)	Impact on virus replication (minor allele)	Impact on adaptive immune functions (minor allele)	Reference
IFNL4^a(IFNL3)	rs12979860	Major: C/CMinor: C/T, T/T	—	Reducing IFNL3	HCV: reduced IFN-α treatment response, lower rates of spontaneous clearance		49, 71–75
					Acute CMV: reduced replication
None^b	rs8099917	Major: T/TMinor: T/G, G/G	—	Reducing IFNL3	HCV: reduced IFN-α treatment response, lower rates of spontaneous clearance	Acute CMV: less priming of CMV-specific T cells	71–74
					Acute CMV: reduced replication
IFNL4^a	rs10853727	Major: A/A		?	-	Higher post-vaccine measles titers	76
(IFNL3)		Minor: A/G, G/G
IFNL4	ss469415590	Major: T/T	CDR	Frameshift, causing IFNL4 expression	HCV: reduced IFN-α treatment response, lower rates of spontaneous clearance	?	20, 21
	(rs368234815)	Minor: T/ΔG, ΔG/ΔG
IFNLR1	rs10903035	Major: A/AMinor: G/A, G/G	3′ UTR	?	HCV: reduced IFN-α treatment response, lower rates of spontaneous clearance	?	77

a Originally some SNPs were assigned to or close to IFNL3; however, with the discovery of IFNL4,²¹ there are various changes. We show both locations, although the rs129 79860 and the rs10853727 have their ‘true’ location in IFNL4.

b Originally the SNP rs8099917 has been assigned to IFNL3; however, its true location is between IFNL4 and IFNL4P1.

?, not known.

Figure 3 Hypothesis of IFNL3 single nucleotide polymorphism and impact on virus replication. The left panel shows a major allele genotype with a presumed fully functional IFNL3 expression during virus replication. The right shows a minor allele genotype with reduced IFNL3 expression, but increased IFNL4 expression. The genotype results in a significantly different ISG background expression which may be an advantage or disadvantage for different viruses.

Figure 4 Impact of IFNL on Th1/Th2 cytokine profiling. The IFNL3 major allele genotype shows a predominant polarization to a macrophage M1 phenotype, whereas the minor allele genotype may show a relative increase of M2 phenotype. These macrophage phenotypes are associated with the downstream regulation and polarization of Th1 and Th2 cells. NK cells, natural killer cells.

Prokunina-Olsson L, Muchmore B, Tang W et al.A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet2013;45: 164–171.

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