Effective intrahepatic CD8＋ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes

Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8＋ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8＋ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin （Ova） as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.

A dominant insulin-specific and islet-destructive T-cell response is sufficient to activate CD8 T cells directed against the fatty-acid receptor GPR40

Type 1 diabetes mellitus(T1D)is an autoimmune disease that is characterized by a progressive infiltration of autoreactive T cells into the pancreatic islets and the destruction of insulin-producing beta cells.1 It is generally assumed that T1D is initiated by yet unidentified T cells that escape from thymic negative selection2 and trigger an initial destruction of beta cells.3 These initial hits could generate suitable conditions in beta cells and/or in islets that favor the coactivation and amplification of autoreactive T cells directed against a broad spectrum of beta cell-specific antigens,such as GAD65,IGRP,and IA-2.