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 2

Adult mice show increased macrophage-associated lymphocyte organization, parenchymal lymphocyte clustering and IgG+ B cells compared to young mice.

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Adult mice show increased macrophage-associated lymphocyte organization,...
(A) Representative images (original magnification, ×10) of macrophage (green; F4/80) and nuclei (DAPI; blue) staining of adult (top) and young (bottom) HBVEnvRag1–/– mouse liver tissue prior to adoptive transfer. (B–E) Representative images (original magnification, ×10) of F4/80 (green), DAPI (blue), and CD4 (red; B), CD8 (red; C), B cells (red; B220; D) or DCs (red; CD11c; E) staining of adult and young HBVEnvRag1–/– liver tissue 8 days after adoptive transfer of adult WT splenocytes. Livers were frozen in OCT, sectioned at 6-μm thickness, and acetone fixed. (G–I) 15 random frames per section of n ≥ 3 mice per group were scored by an unbiased pathologist for (G) number of macrophage clusters, defined as ≥4 macrophages adjacent to each other/frame; (H) number of CD4+, CD8+, B220+, or CD11c+ cells interacting with macrophage cluster/frame; and (I) number of parenchymal CD4+, CD8+, B220+ lymphocyte clusters/frame (≥2 cells within 15 μm). (F) Representative images (original magnification, ×10) of IgM (green), IgG (red; pooled IgG1 and IgG2b), and DAPI (blue) staining of adult and young liver tissue 21 days after adoptive transfer. (J) 15 random frames per section of n ≥ 3 mice per group were scored by an unbiased pathologist for number of IgM+ cells, IgG+ cells, and IgG clusters per frame (≥2 cells within 15 μm). Scale bars: 30 μm. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired 2-tailed Student’s t test.