Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes

Abstract

Both hepatitis B and C viruses frequently establish chronic infection, raising the question whether T cells are poorly primed in the liver. To determine the role of different cell types in the activation of CD81 T cells against hepatocellular antigens, we used an Adeno-associated virus to deliver ovalbumin to hepatocytes. In contrast to CD81 T cells, CD41 T cells were not activated. The CD81 T cells were activated even in the absence of endogenous CD41 T cells; however, in the liver, these cells were high in the programmed death-1 protein and low in CD127. Chimera experiments revealed that these CD81 T cells were activated on a solid tissue cell. Conclusion: Priming of CD81 T cells directly on nonhematopoietic cells, in the absence of CD41 T cell help, results in suboptimal T cell activation. This could explain the impaired function of CD81 T cells seen in chronic liver infection.

Intrahepatic Activation of Naive CD4+ T Cells by Liver-Resident Phagocytic Cells

“…One possibility is that hepatocytes fail to generate a functional OT-II epitope as the result of proteolytic cleavage of the peptide recognized by OT-II T cells. This might explain why DO11.10-Tg T cells that recognize the same nine-residue peptide as OT-II T cells (37) also were not activated in the liver of mice treated with rAAV.OVA (16). However, the occasional activation of OT-II T cells that we detected in the liver-draining LNs of a few of our rAAV-treated mice argue against this possibility, at least in the case of vectors used in the current study.…”

“…Previous studies showed that OT-II and D0.10.11 TCR-Tg CD4 + T cells failed to be activated in mice that expressed OVA by transgenesis or by rAAV-mediated transduction (13,15,16), suggesting that the liver cannot support primary activation of naive CD4 + T cells. To exclude the possibilities that these findings were either due to tolerance to OVA caused by Ag expression from birth or the low-transduction efficacy of type 2 adeno-associated virus (AAV) vectors resulting in a limited amount of Ag available for presentation, we used rAAV vectors pseudotyped to type 8 capsid that were shown to mediate efficient transduction of 100% of hepatocytes in adult mice (17)(18)(19).…”

“…12), but primary CD4 + T cell activation in the liver has never been demonstrated in vivo. In studies in which OVA-specific CD4 + T cells (from TCRtransgenic [Tg] OT-II and D0.10.11 mice) were adoptively transferred into mice expressing OVA in the liver, intrahepatic activation or retention of donor CD4 + T cells was not observed (13)(14)(15)(16). These studies led to the conclusion that naive CD4 + T cells cannot undergo primary activation within the liver, and this was consistent with the paradigm of naive CD4 + T cell homing and activation being restricted to lymphoid organs.…”

“…These studies led to the conclusion that naive CD4 + T cells cannot undergo primary activation within the liver, and this was consistent with the paradigm of naive CD4 + T cell homing and activation being restricted to lymphoid organs. Based on these experiments, it was hypothesized that lack of provision of CD4 help in the liver contributes to failure to develop optimal CD8 + T cell function (13)(14)(15)(16).…”

Regulation of the Intrahepatic CD8+ T Lymphocyte

“…It is well known that the liver has a lower CD4 + :CD8 + T cell ratio compared to most other organs, which may be a reason for the formation of a tolerogenic environment 105 . Other groups have shown that CD8 + T cells can be directly primed by DCs without CD4 + T cell help 106 , but functional CD4 + T cells or at least IL-2 are needed to optimize CD8 + T cell effector function 30,107,108 . Treatment of virally anergized CD8 + T cells with exogenous IL-2 also leads to an increase in CD25 expression, and it has been shown that IL-10 treatments can decrease CD25 expression possibly contributing to T cell anergy 109,110 .…”