The level of antigen expression in the liver predicts the fate and functional outcome of antigen-specific CD8 T cells (LYM5P.706)

A wide spectrum of CD8 T cell responses can be elicited against antigens (Ag) expressed in the liver, ranging from tolerance to full effector function. Identifying the factors involved would allow us to predict the outcome of liver transplantation and viral hepatitis. To investigate how CD8 T cells respond to liver Ags, we have developed recombinant adeno-associated viral vectors that, when injected into mice, allow de novo Ag expression in a variable number of hepatocytes. Within the first day of Ag expression by at least 70% of hepatocytes, most naïve Ag-specific CD8 T cells were activated in the liver via direct presentation by hepatocytes. CD8 T cell activation in lymph nodes and spleen via cross presentation was detected a day later, suggesting that primary activation of CD8 T cells against hepatocyte-expressed Ag is compartmentalised. These T cells proliferated, developed into CTLs in the first week but were unable to kill all Ag-expressing hepatocytes. Most effector T cells were rapidly deleted while those surviving became exhausted and unresponsive over time. In contrast, when less than 10% of hepatocytes expressed the targeted Ag, CD8 T cell were gradually activated in liver and lymphoid tissues but were not deleted. Instead, they eliminated all Ag-expressing hepatocytes and maintained their effector function overtime. In summary, this study shows that intrahepatic Ag load dictates both the fate and function of CD8 T cells recognising hepatocyte-expressed Ags.