Peripheral immunization induces functional intrahepatic Hepatitis C specific immunity following selective retention of vaccine-specific CD8 T cells by the liver: Immunization induced intrahepatic HCV-specific immunity

Krystle A. Lang Kuhs, Roberta Toporovski, Arielle A. Ginsberg, Abby L. Olsen, Devon J. Shedlock, Matthew P. Morrow, Jian Yan, Rebecca G. Wells, David B. Weiner

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

It is believed that an effective HCV vaccine must induce strong HCV-specific cytotoxic IFNγ + CD8 + T cells able to migrate into and become fully activated within the liver, an organ known to suppress T-cell responses and induce tolerance. Given the importance of intrahepatic HCV-specific T cells in the clearance of acute infection, the goal of this present study was to determine if peripheral immunization was able to induce functional intrahepatic HCV-specific T cell-based immunity both in the presence and absence of HCV antigen expression within the liver. Using a novel HCV NS3/NS4A DNA vaccine, we show that peripheral immunization of C57BL/6 mice results in the formation of a large pool of fully functional HCV-specific cytotoxic IFNγ + CD8 + T cells within the liver and that these cells were highly enriched within the liver as compared with the spleen. Following hepatic expression of cognate HCV antigen using a previously described liver transfection method, we show that this pool of vaccine-induced HCV-specific CD8 + T cells retained its ability to become highly activated as shown by the upregulation of IFNγ and CC R5 expression, as well as by the clearance of HCV NS3 expressing hepatocytes. Taken together, these findings suggest that T-cell effector function is preserved within the liver and that selective recruitment of antigen-specific T cells to the liver may play a previously unappreciated role in the process of immune surveillance, which may be exploited for future T cell-based HCV vaccines.

Original languageEnglish
Pages (from-to)1326-1335
Number of pages10
JournalHuman Vaccines
Volume7
Issue number12
DOIs
StatePublished - Dec 2011

Bibliographical note

Funding Information:
This manuscript was supported in part by funding from the NIH to DBW and from Inovio pharmaceuticals, as well as, a grant from the state of Pennsylvania. The authors note possible commercial conflicts associated with this work, which may include; Wyeth, Inovio, BMS, Virxsys, Ichor, Merck, VGXi and Aldeveron.

Keywords

  • Consensus
  • HCV DNA vaccine
  • Liver transfection
  • NS3
  • NS4A

ASJC Scopus subject areas

  • General Pharmacology, Toxicology and Pharmaceutics
  • Immunology

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