Research Paper

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

Volume 7, Issue 12   December 2011
Pages 1326 - 1335
http://dx.doi.org/10.4161/hv.7.12.18279
Keywords: HCV DNA vaccine, NS3, NS4A, consensus, liver transfection
Authors: Krystle A. Lang Kuhs, Roberta Toporovski, Arielle A. Ginsberg, Abby L. Olsen, Devon J. Shedlock, Matthew P. Morrow, Jian Yan, Rebecca G. Wells and David B. Weiner

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Abstract:
It is believed that an effective HCV vaccine must induce strong HCV-specific cytotoxic IFN-γ+ 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 IFN-γ+ CD8+ T cells within the liver and that these cells were highly enriched within the liver as compared to 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 IFN-γ and CCR5 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.

Received: May 16, 2011; Accepted: October 2, 2011

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