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

Lang Kuhs KA, Toporovski R, Ginsberg AA, Olsen AL, Shedlock DJ, Morrow MP, Yan J, Wells RG, Weiner DB
Hum Vaccin. 2011 7 (12): 1326-35

PMID: 22108033 · PMCID: PMC3338931 · DOI:10.4161/hv.7.12.18279

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.

MeSH Terms (16)

Animals Carrier Proteins CD8-Positive T-Lymphocytes Female Hepacivirus Hepatitis C Humans Interferon-gamma Liver Mice Mice, Inbred C57BL T-Lymphocytes, Cytotoxic Transfection Vaccination Vaccines, DNA Viral Nonstructural Proteins

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