Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B
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
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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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 4

Age-dependent hepatic CXCL13 expression is by macrophages and is susceptible to clodronate liposome treatment.

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Age-dependent hepatic CXCL13 expression is by macrophages and is suscept...
(A) Cxcl13 mRNA expression relative to Gapdh in 3- and 8-week-old Rag1–/– mouse liver, spleen, MLNs, and HLNs. (n ≥ 4). Data are representative of 2 independent experiments. (B) Relative Cxcl13 mRNA expression from liver of WT mice at the indicated ages. Data are representative of 2 independent experiments. (C) Cxcl13 mRNA expression levels in whole liver of adult and young Rag1–/– mice and in sorted cell populations from adult Rag1–/– liver. Cells were isolated using liver perfusion with DNAse and collagenase, followed by gradient separation and sorting for viability and the following parameters: NK cells (NK1.1+), DCs (NK1.1–CD11c+CD11b–), granulocytes/monocytes (NK1.1–CD11b+F4/80–). Macrophages were enriched by liver perfusion with DNase and collagenase followed by 30-minute incubation with pronase, isolated using a 25:50 Percoll gradient and sorted for CD45+CD11b+F4/80+. Hepatocytes were isolated and sorted by flow cytometry based on size and viability. (D) Cxcl13 mRNA expression in unsorted macrophage-enriched fractions from liver of Rag1–/– mice aged 3, 5, and 8–12 weeks (n = 3). (E) Relative CXCL13 levels in whole liver and macrophage-enriched fractions from adult Rag1–/– mice that were untreated or treated with clodronate 48 hours earlier (data are representative of 3 independent experiments). *P < 0.05, **P < 0.01, ***P < 0.001, Mann-Whitney test (A) or Tukey’s ANOVA multiple-comparison test (B and D).