Liver-Resident CD103+ Dendritic Cells Prime Antiviral CD8+ T Cells In Situ

Abstract

The liver maintains a tolerogenic environment to avoid unwarranted activation of its resident immune cells upon continuous exposure to food and bacterially derived antigens. However, in response to hepatotropic viral infection, the liver’s ability to switch from a hyporesponsive to a pro-inflammatory environment is mediated by select sentinels within the parenchyma. To determine the contribution of hepatic DCs to activate naïve CD8+ T cells, we first characterized resident DC subsets in the murine liver. Liver DCs exhibit unique properties, including the expression of CD8α (traditionally lymphoid tissue specific), CD11b and CD103 markers. In both steady-state and following viral infection, liver CD103+ DCs express high levels of MHC-II, CD80 and CD86, and contribute to the high number of activated CD8+ T cells. Importantly, viral infection in the Batf3−/− mouse, which lacks CD8α+ and CD103+ DCs in the liver, exhibits a three-fold reduction in the proliferative response of antigen-specific CD8+ T cells. Limiting DC migration out of the liver does not significantly alter CD8+ T cell responsiveness, indicating that CD103+ DCs initiate the induction of CD8+ T cell responses in situ. Collectively, these data suggest that liver resident CD103+ DCs are highly immunogenic in response to hepatotropic viral infection and serve as a major APC to support the local CD8+ T cell response. It also implies that CD103+ DCs present a promising cellular target for vaccination strategies to resolve chronic liver infections.

The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development

“…Nevertheless, if immunity is required as a response to for example pathogens either monocyte-derived DCs present in intrahepatic myeloid-cell aggregates for T cell population expansion (iMATEs) provide bases for efficient T cell responses (18) or cytotoxic T lymphocytes are generated by migratory DCs reaching the draining LN (19, 20). On the other side of the immune spectrum, migratory DCs are likely involved in the generation of regulatory T cells toward dietary antigens in the liver-draining LN (21).…”

“…Thus, the lymphatic circulation of liver-resident DCs and the circulating DC translocation might contribute to important peripheral tolerogenic responses under steady state. The major migratory cell population is the cDC1 (CD11c + CD103 + CD11b − ) cells, and it remains to be elucidated whether monocyte-derived DCs or cCD2 (CD11c + CD103 − CD11b + ) cells contribute to the migratory cell population under differing circumstances (20, 27). …”

Intrahepatic regulation of antiviral T cell responses at initial stages of viral infection

“…However, liver DCs become immunogenic in response to hepatotropic viral infection and act as APCs to support CD8 T cell responses in the liver [7]. Liver-resident CD103 + DCs are potent APCs and strongly prime antiviral CD8 T cells in situ [7].…”

“…However, liver DCs become immunogenic in response to hepatotropic viral infection and act as APCs to support CD8 T cell responses in the liver [7]. Liver-resident CD103 + DCs are potent APCs and strongly prime antiviral CD8 T cells in situ [7]. In addition, DC-derived IL-23 increases HBsAg-stimulated differentiation of naive CD4 T cells into Th17 cells and exacerbates liver inflammation [63].…”

“…CXCL10 and IL-7) [3–5]. The liver resident cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs) can function as antigen-presenting cells (APCs) to prime naïve T cells, although the effect is not potent as that of liver CD103 + dendritic cells (DCs) [6, 7]. Other liver resident and infiltrated lymphocytes, including natural killer (NK) cells, NKT cells, γδ T cells and innate lymphoid cells (ILCs) can control viral replication and regulate T cell functions through producing cytokines and granules, such as IFN-γ, IL-17, granzyme B and perforin [8–11].…”