Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3728-3739. https://doi.org/10.1172/JCI68182.
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Research Article Immunology

Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Abstract

Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

Authors

Jean Publicover, Anuj Gaggar, Stephen Nishimura, Christine M. Van Horn, Amanda Goodsell, Marcus O. Muench, R. Lee Reinhardt, Nico van Rooijen, Adil E. Wakil, Marion Peters, Jason G. Cyster, David J. Erle, Philip Rosenthal, Stewart Cooper, Jody L. Baron

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Figure 1

HBV-specific immune responses that direct viral clearance are first detected in the liver.

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HBV-specific immune responses that direct viral clearance are first dete...
(A–L) HBV-specific T cell responses from lymphocytes isolated from the liver (A, E, and I), HLNs (B, F, and J), spleen (C, G, and K), and MLNs (D, H, and L) at days 3 (A–D), 8 (E–H), and 12 (I–L) after adoptive transfer of adult WT syngeneic splenocytes into adult HBVEnvRag1–/– mice. Lymphocytes were stimulated with pools of HBV-envelope–derived peptides (15-mer peptides; pools of 12–14). IFN-γ was measured by ELISpot assay; representative data from 2 separate experiments are shown. Samples were pooled from n ≥ 3 mice. Pool 0 denotes no peptide; solid lines denote baseline IFN-γ levels; arrowheads denote a positive response ≥2× that of baseline. (M and N) Il21 mRNA expression levels from lymphocytes isolated from adult HBVEnvRag1–/– and Rag1–/– liver, spleen, MLNs, HLNs, and ILNs at 3 (M) and 8 (N) days after adoptive transfer of WT syngeneic splenocytes. Il21 levels relative to Gapdh were determined by real-time PCR. Data are representative of at least 2 independent experiments. **P = 0.0048, unpaired 2-tailed Student’s t test.