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
View: Text | PDF
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

×

Figure 6

Absence of CXCR5 on donor splenocytes alters hepatic IgM+ and IgG+ B cell number and B cell clustering.

Options: View larger image (or click on image) Download as PowerPoint
Absence of CXCR5 on donor splenocytes alters hepatic IgM+ and IgG+ B cel...
(A) Frequency of B cells (plasma cells and plasmablasts) determined by FACS analysis on liver lymphocytes isolated 3 weeks after transfer of HBVEnvRag1–/– or Rag1–/– mice with WT or Cxcr5–/– splenocytes. Percentage of IgG1, IgG2b, and IgG3 B cell (B220loTCR-β–CD44hi) and IgM B cell (B220loTCR-β–) populations were identified in liver-derived lymphocytes by FACS (n = 3). (B) Representative images (original magnification, ×10) from liver tissue of HBVEnvRag1–/– mice 21 days after adoptive transfer of WT or Cxcr5–/– splenocytes, stained for IgM (green), IgG (red; IgG1 and IgG2b pooled) and DAPI (blue). (C and D) 15 random frames per section of n ≥ 3 mice per group were blinded and analyzed for (C) number of IgM+ and IgG+ cells and (D) number of IgG lymphocyte clusters (≥2 cells within 15 μm) and IgG+ cells associated with ≥1 IgM+ cell per frame. (E) Representative image (original magnification, ×40) from HBVEnvRag1–/– mouse liver stained for F4/80 (green), IgG (red; IgG1 and IgG2b pooled), and DAPI (blue) 21 days after adoptive transfer of WT syngeneic splenocytes. Scale bars: 30 μm (B); 10 μm (E). *P < 0.05, **P < 0.01, ***P < 0.001, Tukey’s ANOVA multiple-comparison test (A) or unpaired 2-tailed Student’s t test (C and D).