Liver Is Able to Activate Naïve CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System

Abstract

The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8+ T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8+ T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8+ T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8+ T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8+ T cell response and accounts for the dysfunctional CD8+ T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection.

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

“…Previous studies have shown that CD8 + T cell priming by alloantigen in the liver results in apoptotic death of CD8 + T cells and non-productive effector function whereas priming in peripheral lymph nodes promotes competent CD8 + T cell effector function 22,40 . To determine if rejection of allogeneic hepatocytes transplanted to the liver by direct portal injection requires priming in peripheral lymph nodes, we assessed graft survival in recipients that lack lymph nodes (Ltα KO mice, H-2 b ).…”

Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8+ T Cell-mediated Hepatic Antiviral Immunity

“…Mononuclear cells were isolated from livers according to previous work. 35,47,48 Briefly, livers were flushed via the portal vein with 0.05% collagenase IV (Sigma-Aldrich) in 1× phosphate-buffered saline (PBS) and washed with Iscove's modified Dulbecco's medium containing 10% newborn calf serum. Liver tissue was then homogenized and further digested with 0.05% collagenase IV in 1× PBS.…”

Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance

“…It remains unclear why surveillance occasionally fails, e.g., against hepatitis B virus-associated (HBV-associated) or hepatitis C virus-associated (HCV-associated) hepatocellular carcinoma (HCC). Possible reasons could be an initial failure to induce effective T cells (3)(4)(5), T cell exhaustion due to chronic antigen stimulation (6,7), tumor-induced tolerance (8), immune escape by loss of immunogenicity (9), or tumor development in tolerogenic organs, e.g., the liver (10). In humans, T cell responses appear to be more efficient in those individuals who completely cleared the virus (11,12); however, it is difficult to identify individuals in the acute infection phase (4,12).…”