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A 7-Amino Acid Peptide Mimic from Hepatitis C Virus Hypervariable Region 1 Inhibits Mouse Lung Th9 Cell Differentiation by Blocking CD81 Signaling during Allergic Lung Inflammation.

ABSTRACT: T helper (Th) cells orchestrate allergic lung inflammation in asthma pathogenesis. Th9 is a novel Th cell subset that mainly produces IL-9, a potent proinflammatory cytokine in asthma. A 7-amino acid peptide (7P) of the hypervariable region 1 (HVR1) of hepatitis C virus has been identified as an important regulator in the type 2 cytokine (IL-4, IL-5, and IL-13) immune response. However, it is unknown whether 7P regulates Th9 cell differentiation during ovalbumin- (OVA-) induced allergic lung inflammation. To address this, we studied wild-type mice treated with 7P and a control peptide in an in vivo mouse model of OVA-induced allergic inflammation and an in vitro cell model of Th9 differentiation, using flow cytometry, cytokine assays, and quantitative PCR. The binding of 7P to CD81 on naïve CD4+ T cells during lung Th9 differentiation was determined using CD81 overexpression and siRNA knockdown analyses. Administration of 7P significantly reduced Th9 cell differentiation after OVA sensitization and exposure. 7P also inhibited Th9 cell differentiation from naïve and memory CD4+ T cells in vitro. Furthermore, 7P inhibited the differentiation of human Th9 cells with high CD81 expression from naïve CD4+ T cells by blocking CD81 signaling. CD81 siRNA significantly reduced Th9 cell differentiation from naïve CD4+ T cells in vitro. Interestingly, CD81 overexpression in human naïve CD4+ T cells also enhanced Th9 development in vitro. These data indicate that 7P may be a good candidate for reducing IL-9 production in asthma.

SUBMITTER: Zhao W

PROVIDER: S-EPMC7109583 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A 7-Amino Acid Peptide Mimic from Hepatitis C Virus Hypervariable Region 1 Inhibits Mouse Lung Th9 Cell Differentiation by Blocking CD81 Signaling during Allergic Lung Inflammation.

Zhao Wanzhou W Tan Conghao C Yu Xi X Yu Ruihe R Mei Qibing Q Cheng Yun Y

Journal of immunology research 20200320

T helper (Th) cells orchestrate allergic lung inflammation in asthma pathogenesis. Th9 is a novel Th cell subset that mainly produces IL-9, a potent proinflammatory cytokine in asthma. A 7-amino acid peptide (7P) of the hypervariable region 1 (HVR1) of hepatitis C virus has been identified as an important regulator in the type 2 cytokine (IL-4, IL-5, and IL-13) immune response. However, it is unknown whether 7P regulates Th9 cell differentiation during ovalbumin- (OVA-) induced allergic lung inf ...[more]

PMID: 32258172

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Project description:Hypervariable region 1 (HVR1) (amino acids [aa] 384 to 410) on the E2 glycoprotein of hepatitis C virus contributes to persistent infection by evolving escape mutations that attenuate binding of inhibitory antibodies and by blocking access of broadly neutralizing antibodies to their epitopes. A third proposed mechanism of immune antagonism is that poorly neutralizing antibodies binding to HVR1 interfere with binding of other superior neutralizing antibodies. Epitope mapping of human monoclonal antibodies (HMAbs) that bind to an adjacent, conserved domain on E2 encompassing aa 412 to 423 revealed two subsets, designated HC33 HMAbs. While both subsets have contact residues within aa 412 to 423, alanine-scanning mutagenesis suggested that one subset, which includes HC33.8, has an additional contact residue within HVR1. To test for interference of anti-HVR1 antibodies with binding of antibodies to aa 412 to 423 and other E2 determinants recognized by broadly neutralizing HMAbs, two murine MAbs against HVR1 (H77.16) and aa 412 to 423 (H77.39) were studied. As expected, H77.39 inhibited the binding of all HC33 HMAbs. Unexpectedly, H77.16 also inhibited the binding of both subsets of HC33 HMAbs. This inhibition also was observed against other broadly neutralizing HMAbs to epitopes outside aa 412 to 423. Combination antibody neutralization studies by the median-effect analysis method with H77.16 and broadly reactive HMAbs revealed antagonism between these antibodies. Structural studies demonstrated conformational flexibility in this antigenic region, which supports the possibility of anti-HVR1 antibodies hindering the binding of broadly neutralizing MAbs. These findings support the hypothesis that anti-HVR1 antibodies can interfere with a protective humoral response against HCV infection.HVR1 contributes to persistent infection by evolving mutations that escape from neutralizing antibodies to HVR1 and by shielding broadly neutralizing antibodies from their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines.

Dataset Information

A 7-Amino Acid Peptide Mimic from Hepatitis C Virus Hypervariable Region 1 Inhibits Mouse Lung Th9 Cell Differentiation by Blocking CD81 Signaling during Allergic Lung Inflammation.

Publications

A 7-Amino Acid Peptide Mimic from Hepatitis C Virus Hypervariable Region 1 Inhibits Mouse Lung Th9 Cell Differentiation by Blocking CD81 Signaling during Allergic Lung Inflammation.

Similar Datasets

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