Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Antigen expression level dictates the outcome of CD8+ T cell responses against antigens expressed in the liver (#93)

Yik Chun (Michael) Wong 1 , Szun Szun Tay 1 2 3 , David M. McDonald 1 , Nicole A. W. Wood 1 , Ben Roediger 2 , Frederic Sierro 1 , Claire McGuffog 1 , Ian E. Alexander 3 , Wolfgang Weninger 2 4 , Geoffrey W. McCaughan 1 , David G. Bowen 1 , Patrick Bertolino 1
  1. Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, NSW, Australia
  2. Immune Imaging Group, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, NSW, Australia
  3. Gene Therapy Research Unit, Children's Medical Research Institute and Children's Hospital at Westmead, Sydney, NSW, Australia
  4. Discipline of Dermatology, University of Sydney, NSW, Australia

A wide spectrum of CD8+ T cell responses can be elicited against antigens expressed in the liver, ranging from tolerance/unresponsive to full effector function. Identifying the factors involved could have implications for understanding and predicting the outcome of liver transplantation and viral hepatitis. Here we established a mouse model utilising recombinant adeno-associated viral vectors to investigate how CD8+ T cells respond to antigens expressed in hepatocytes.

We found that within 24 hours of antigen expression by at least 70% of hepatocytes, many naive antigen-specific CD8+ T cells were activated in the liver via direct presentation by hepatocytes. This was followed by CD8+ T cell activation in the lymph nodes and the spleen via cross presentation a day later. This suggests that primary activation of CD8+ T cells against hepatocyte-expressed antigen is compartmentalised in the first two days. These activated CD8+ T cells proliferated and developed into cytotoxic T cells in the first week. However, antigen-expressing hepatocytes were not completely cleared and the CD8+ T cells became exhausted and unresponsive over time.

In contrast, when less than 10% of hepatocytes expressed the targeted antigen, there was a more gradual activation of CD8+ T cells in the liver. Cross presentation in the lymph nodes and the spleen was also delayed. Nevertheless, these CD8+ T cells proliferated and became functional. They eliminated all antigen-expressing hepatocytes and their effector functions were maintained. Importantly, the exhaustion phenotype of the CD8+ T cells was not irreversibly imprinted during initial activation, but required continuous exposure to a high level of the intrahepatic antigen.

In summary, this study shows that intrahepatic antigen load dictates the fate of CD8+ T cell responses to liver-expressed antigens.