Distinct kinetics and dynamics of cross-presentation in... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells#

Schurich, Anna1; Böttcher, Jan P.1; Burgdorf, Sven1; Penzler, Patrick2; Hegenbarth, Silke1; Kern, Michaela1; Dolf, Andreas1; Endl, Elmar1; Schultze, Joachim3,4; Wiertz, Emmanuel5¶; Stabenow, Dirk1; Kurts, Christian1; Knolle, Percy1*†

1 Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany

2 Institute for Applied Mathematics, LIMES Institute, University of Bonn, Bonn, Germany

3 Laboratory for Genomics and Immunoregulation, LIMES Institute, University of Bonn, Bonn, Germany

4 Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands

5 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands

Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands

* Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany

Email:[email protected]

Received February 3, 2009; accepted May 7, 2009.

Published online 16 July 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Deutsche Forschungsgemeinschaft; Grant Numbers: SFB 704 GRK 804; Grant sponsor: BONFOR.

# Potential conflict of interest: Nothing to report.

fax: +49-228-2871-1052.

Additional Supporting Information may be found in the online version of this article.

Abstract

Cross-presentation is an important function of immune competent cells, such as dendritic cells (DCs), macrophages, and an organ-resident liver cell population, i.e., liver sinusoidal endothelial cells (LSECs). Here, we characterize in direct comparison to DCs the distinct dynamics and kinetics of cross-presentation employed by LSECs, which promote tolerance induction in CD8 T cells. We found that LSECs were as competent in cross-presenting circulating soluble antigen ex vivo as DCs at a per-cell basis. However, antigen uptake in vivo was 100-fold more pronounced in LSECs, indicating distinct mechanisms of cross-presentation. In contrast to mannose-receptor–mediated antigen uptake and routing into stable endosomes dedicated to cross-presentation in DCs, we observed distinct antigen-uptake and endosomal routing with high antigen turnover in LSECs that resulted in short-lived cross-presentation. Receptor-mediated endocytosis did not always lead to cross-presentation, because immune-complexed antigen taken up by the Fc-receptor was not cross-presented by LSECs, indicating that induction of CD8 T cell tolerance by LSECs is impaired in the presence of preexisting immunity. Conclusion: These results provide a mechanistic explanation how organ-resident LSECs accommodate continuous scavenger function with the capacity to cross-present circulating antigens using distinct kinetics and dynamics of antigen-uptake, routing and cross-presentation compared to DCs. (Hepatology 2009.)

Copyright © 2009 American Association for the Study of Liver Diseases.