HBV immune tolerance of HBstransgenic mice observed through parabiosis with WT mice.

It was extensively recognized that central tolerance to HBV exists in HBstransgenic (Tg) mice, however, the immune response to HBV vaccine may be inspired in adult HBs-Tg mice after boosting with potent adjuvants, leaving a mystery to explore its immune tolerance. Here, WT-HBs-Tg parabiotic mice model was generated by conjoining WT (donor) and HBs-Tg (host) mouse via parabiotic surgery, in order to see how immunocompetent WT mice naturally respond to HBV, and how tolerant HBs-Tg mice influence the anti-HBV immunity from WT mice. It was found that WT CD8⁺ T cells markedly accumulated into the liver of HBs-Tg parabionts, and importantly, almost all HBsAg-specific CD8⁺ T cells derived from WT but not HBs-Tg mice, making a clear separation of a normal immune response from WT donor and a tolerant response by recipient host. Further, in the absence of host but not donor spleen, HBsAg-specific CD8⁺ T cells disappeared, indicating that host spleen was the indispensable site for donor HBsAg-specific CD8⁺ T cell priming though its mechanisms need further study. We found that donor CD4⁺ T helper cells were necessary for donor HBsAg-specific CD8⁺ T cell response by CD4-deficiency in WT or in HBs-Tg mice, indicating that an immune response was elicited between CD4⁺ T helper cells and CD8⁺ cytotoxic T cells of donor in the host but not donor spleen. It was noted that compared to donor CD4⁺ T cells, host CD4⁺ T cells were characterized with more tolerant features by harboring more CD25⁺Foxp3⁺ Tregs with higher expression of PD-1 and TIGIT in the spleen of HBs-Tg parabionts, which exhibited suppressive function on CD8⁺ T cells directly. Moreover, the Th1/Treg ratio was enhanced after parabiosis, suggesting that donor T helper cells may overcome the negative regulation of host Tregs in host spleen. In conclusion, both incompetent anti-HBV CD8⁺ T cells and insufficient help from CD4⁺ T cells are the major mechanisms underlying immune tolerance in HBs-Tg mice which helps explain HBV persistence. [ABSTRACT FROM AUTHOR]