Maternal HBV infection induces HBVeAg/PD-L1 dependent tolerance in offspring

Hepatitis B virus (HBV) can be vertically transmitted from mother to babies. Unlike exposure at adulthood, immunological consequences of such exposure to HBV in newborns is "tolerance" to chronic HBV infection.

Ordinarily mice are not naturally infected with HBV. New paper in Immunity reported development of mouse model to study immunology of vertical transmission of HBV.

This model is a combination of two independent processes: 1st, use of HBV transgenic mice and 2nd, hydrodynamic injection of plasmid that contained 1.3-mer HBV genomic DNA. Initially, the authors showed mice born to HBV Tg females (referred here as TGD mouse), but not controls, developed "chronic HBV infection" when exposed to HBV plasmid. 

  

Analysis of HBV-specific CD8 T cells from HBV-DNA injected TGD mice liver showed up-regulation of checkpoint inhibitor PD-1 on T cells.

Treatment of TGD mice with anti-PDL1 antibody enabled them to control HBV-DNA infection.

Moreover, the authors found that clodronate-liposome depletion of macrophages from TGD mice also enabled them to control HBV-DNA infection.

Finally, the authors found that HBVeAg played important role in viral persistence and tolerance by observing that (a) mice born to HBV-mut Tg females (HBV lacking eAg) do not develop persistent HVB-DNA infection, and (b) TGD mice exposed to HBV-DNA lacking eAg also were able to eliminate virus.

In summary, this study suggests that HBVeAg controls newborn's tolerance to HBV via inhibitory PD-L1 signaling.

Few additional thoughts: first, the authors reported that after HBV-DNA injection, around 15% of liver macrophages, called Kupffer cells, expressed viral antigen. However, they also found that >75% of Kupffer cells expressed PD-L1 upon HBV-DNA injection. Second, since HBV virus from HBV Tg pregnant females cannot directly infect newborns, it is not clear how HBVeAg is able to modulate macrophages and tolerize newborn's CD8 T cells (the authors also acknowledged this inconsistency).

David Usharauli

Enigma of the peripheral tolerance: CTLA4+ anergic CD8 T cells

When Sir Burnet first proposed clonal-selection theory of everything to explain how immune system could detect non-self antigens while at the same time avoiding autoimmunity, he probably had no idea that his theory would require major and multiple modifications to accommodate new data.

This new study from journal Science is another piece in the puzzle. This work, led by Shimon Sakaguchi at Osaka University, studied self-reactive CD8 T cells from the healthy humans or from vitiligo patients's blood.

The authors studied self-antigen, melanin-specific CD8 T cells. In T cell proliferation assay, Melan-A specific CD8 T cells, almost undetectable before stimulation, undergo robust, multiple-round proliferation and expand to sizable population. However, in presence of regulatory T cells, Melan-A specific CD8 T cells undergo single-round, abortive proliferation.

Tetramer staining indicated that in presence of regulatory T cells, Melan-A specific CD8 T cells mostly consisted of low-affinity clones and displayed anergic phenotype with low cytokine expression (however, please note that small population of CD8 T cells displayed high affinity binding to tetramers even in presence of regulatory T cells. This suggest to me that regulatory T cells suppress proliferation of these high-affinity Melan-A specific CD8 T cells).

Surface staining showed that anergic CD8 T cells generated in presence of T regs express high levels of CTLA-4 and CCR7.

Direct ex vivo analysis of healthy human CD8 T cells showed that naive CD8 T cells consisted of CTLA4+ and CTLA4- population. Antigen-specific or non-specific stimulation of these two population showed that CTLA4+ naive CD8 T cells were (1) enriched in self-specific CD8 T cells, (2) displayed anergic phenotype (abortive proliferation) and (3) preferentially undergo apoptosis in mixed culture.

In summary, the authors showed that healthy human blood contains two types of "naive" CD8 T cell populations: naive, CTLA4neg functionally-competent CD8 T cells and anergic, CTLA4pos functionally-impaired CD8 T cell population.

It appears, though there is no direct evidence, that T regs control self-antigen specific CTLA4+ anergic CD8 T cell development from high-affinity clones. If the model is accurate, then it is not clear why healthy human blood still contains high affinity, self-antigen specific CTLA4- CD8 T cell population (see Fig. 1b tetramer staining. I wonder whether small population of high-affinity CD8 T cells in Treg culture express CTLA4). 

David Usharauli