Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice.
The liver is considered as a unique lymphoid organ favoring the induction of immune tolerance, rather than immunity. Biologists and clinicians alike have a long-standing interest in how the liver induces systemic immune tolerance, but the mechanism has not yet been well elucidated. Here, we employed hepatitis B virus (HBV)-carrier mice generated by hydrodynamically injecting phosphor-adeno-associated virus/HBV1.2 plasmid as a model for adult chronic HBV infection, which we found were unable to respond to hepatitis B surface antigen vaccination. Humoral tolerance induced in HBV-carrier mice could be transferred into Rag1(-/-) mice, because anti-HBV immunity in immunologically reconstituted Rag1(-/-) mice was inhibited by adoptive transfer of splenocytes from HBV-carrier mice. Humoral tolerance needed at least 7 days for induction and persisted to 3 months after a single HBV plasmid injection. Kupffer cell (KC) depletion or interleukin (IL-10) deficiency broke this humoral tolerance, and exogenous injection of IL-10 could effectively induce this tolerance.


CONCLUSIONS
KCs in HBV-carrier mice expressed more IL-10 and mediated the systemic tolerance induction in an IL-10-dependent manner. This previously undescribed humoral tolerance regarding HBV infection will help to explore new approaches to reverse liver-sustained systemic immune tolerance in liver disease.
Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
Long
L
Xu
Wenwei
W
Yin
Rui
R
Sun
Haiming
H
Wei
Zhigang
Z
Tian
D000818:Animals; D002353:Carrier State / Q000276:immunology; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D006509:Hepatitis B / Q000276:immunology* / Q000503:physiopathology; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000502:physiology*; D056724:Immunity, Humoral / Q000502:physiology*; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D018398:Homeodomain Proteins; C064658:RAG-1 protein; D016753:Interleukin-10