IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza

Abstract

Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-λ family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1-cytokines (e.g. IFN-γ), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL-13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor α-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-λs to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses.

Impact of host genetic polymorphisms on vaccine induced antibody response

“…72 Moreover, an IFNL3 SNP (rs8099917) may modulate the humoral immune response after vaccination. 62 Individuals carrying the minor allele in one or both alleles showed an increased seroconversion rate after influenza vaccination. 62 Quantitative real-time PCR investigations have shown, that IFNL3 expression in individuals carrying the minor allele in one or both alleles was lower in PBMCs.…”

“…62 Individuals carrying the minor allele in one or both alleles showed an increased seroconversion rate after influenza vaccination. 62 Quantitative real-time PCR investigations have shown, that IFNL3 expression in individuals carrying the minor allele in one or both alleles was lower in PBMCs. 70 In vitro studies showed that IFNL3 suppressesTh2-cytokines [74][75][76][77] and modulates B-cell function.…”

“…In fact, several independent studies identified a couple of SNPs to influence treatment outcome of infectious disease such as influenza, Hepatitis C virus (HCV), and cytomegalovirus (CMV) as well as the antibody response after vaccination (e.g., influenza, measles). 19,[59][60][61][62] A very prominent example concerns IFN-λ. 63,64 Since 2009, SNPs in IFNL3/4 genes are associated with the HCV treatment outcome.…”

“…70 In vitro studies showed that IFNL3 suppressesTh2-cytokines [74][75][76][77] and modulates B-cell function. 62,78 Although the impact of IFN-λ on immune cells is not yet understood, these studies indicate that IFNL3 is an important regulator of the Th1/Th2 balance and modulates viral clearance/antibody response.…”

Gene–disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections

“…85 As evidence for a potential role of IFN-λs and IFNL SNPs in adaptive immune responses, a study has linked IFNL SNPs with development of effective vaccine response against human influenza virus in immunosuppressed individuals. 86 The study shows that minor allele (G)-carrying individuals at rs8099917 show better vaccine responses (odds ratio = 1.99; P = 0.038) in a dominant model of inheritance, and that T cells from minor allele-carrying individuals produce more IL-4 (a Th2 cytokine). This study also showed that recombinant IFN-λ3 increased Th1 responses from human peripheral blood mononuclear cells while inhibiting Th2 responses (Th2 cytokines are needed for effective seroconversion).…”