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IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):1154-1162. https://doi.org/10.1172/JCI44198.
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Research Article Virology Article has an altmetric score of 5

IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B

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Abstract

HBV is a noncytopathic hepadnavirus and major human pathogen that causes immune-mediated acute and chronic hepatitis. The immune response to HBV antigens is age dependent: viral clearance occurs in most adults, while neonates and children usually develop chronic infection and liver disease. Here, we characterize an animal model for HBV infection that recapitulates the key differences in viral clearance between early life and adulthood and find that IL-21 may be part of an effective primary hepatic immune response to HBV. In our model, adult mice showed higher HBV-dependent IL-21 production in liver, compared with that of young mice. Conversely, absence of the IL-21 receptor in adult mice resulted in antigen persistence akin to that of young mice. In humans, levels of IL-21 transcripts were greatly increased in blood samples from acutely infected adults who clear the virus. These observations suggest a different model for the dichotomous, age-dependent outcome of HBV infection in humans, in which decreased IL-21 production in younger patients may hinder generation of crucial CD8+ T and B cell responses. These findings carry implications for therapeutic augmentation of immune responses to HBV and potentially other persistent liver viruses.

Authors

Jean Publicover, Amanda Goodsell, Stephen Nishimura, Silvia Vilarinho, Zhi-en Wang, Lia Avanesyan, Rosanne Spolski, Warren J. Leonard, Stewart Cooper, Jody L. Baron

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Figure 4

Adult HBVEnvRag recipient mice after adoptive transfer have more CD8+ T cells and TFH cells and elicit a more diverse and long-lived HBV-specific T cell response in the liver.

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Adult HBVEnvRag recipient mice after adoptive transfer have more CD8+ T ...
(A) The frequency of lymphocyte populations from the livers of adult and young HBVEnvRag mice 8 days after splenocyte transfer. TFH cells are defined as CD4+, CXCR5+, ICOS+ cells. B cells are defined as CD19+, B220+ cells. Error bars depict mean ± SEM; n = 4 mice. Statistical significance was determined using the unpaired 2-tailed t test. (B) Frequency of T regulatory cells in adult and young HBVEnvRag mouse liver-derived lymphocytes on days 8 and 21 after transfer of wild-type splenocytes. Samples were pooled from N ≥ 4 mice. Bars show percentages of CD4+-gated cells that are CD25+and FoxP3+. IFN-γ ELISpot results from young and adult HBVEnvRag mouse liver-derived lymphocytes (C) 8 days, (D) 3 months, or (E) 1 year after adoptive transfer. Cells were stimulated with HBV envelope peptide pools as described in Supplemental Figure 3 (pool 0 = no peptide). Dotted and solid lines indicate baseline IFN-γ levels for adult and young mice, respectively. A positive response was considered to be more than twice that of baseline. Lymphocytes were combined 1:1 with Rag1–/– splenocytes (to function as APCs); background IFN-γ levels from splenocytes are indicated by striped bars. Data are representative of at least 2 experiments; samples were pooled from N ≥ 4 mice.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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