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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 5

Liver lymphocytes from adult HBVEnvRag mice after adoptive transfer produce more IL-21 from TFH cells and have increased numbers of IgG-expressing B cells.

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Liver lymphocytes from adult HBVEnvRag mice after adoptive transfer prod...
(A) Il21 mRNA levels relative to those of GAPDH in CD4+ (CD4 enrich) and CD4– (CD4 deplete) fractions from liver-derived lymphocytes or splenocytes of adult or young HBVEnvRag or adult Rag1–/– mice 8 days after adoptive transfer of splenocytes. Error bars depict duplicate wells, samples were pooled from N ≥ 6 mice. (B) IL-21 protein expression determined by ELISpot on liver-derived lymphocytes and splenocytes 8 days after transfer. Samples were pooled from N ≥ 6 mice. (C) Il21 transcripts from unsorted liver lymphocytes, CXCR5–CD4+ sorted cells, CXCR5+CD4+ sorted cells (not determined for Rag1–/– due to low cell number), and CXCR5–CD4– cells from HBVEnvRag and Rag1–/– mice 8 days after transfer. Sorted cells were also CD19–DAPI–. Error bars depict triplicate wells; samples were pooled from N ≥ 4 mice. ND, not determined. (D) Frequency of B cells (plasmablasts and plasma cells) in adults and young HBVEnvRag mice 3 weeks after splenocyte transfer. The left plots show B220 versus CD44 expression on TCRβ– populations, and the right plots show IgM versus IgG1 on TCRβ–, CD44hi, B220lo populations. The percentage of IgG1-, IgG2b-, IgG3-, and IgM-expressing B cells from (E) liver-derived lymphocytes and (F) splenocytes. Error bars depict mean ± SEM; N ≥ 4 mice. Statistical significance was determined using the unpaired 2-tailed t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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