Successful vaccination induces multifunctional memory T-cell precursors associated with early control of hepatitis C virus.
OBJECTIVE
T cells are an important component for development of a vaccine against hepatitis C virus (HCV), but little is known about the features of successful vaccine-induced T cells.


METHODS
We compared the phenotype, function, and kinetics of vaccine-induced and infection-induced T cells in chimpanzees with HCV infection using multicolor flow cytometry and real-time polymerase chain reaction.


RESULTS
In chimpanzees successfully vaccinated with recombinant adenovirus and DNA against HCV NS3-5, HCV-specific T cells appeared earlier, maintained better functionality, and persisted at higher frequencies for a longer time after HCV challenge, than those of mock-vaccinated chimpanzees. Vaccine-induced T cells displayed higher levels of CD127, a marker of memory precursors, and lower levels of programmed death-1 (PD-1) than infection-induced T cells. Vaccine-induced, but not infection-induced, T cells were multifunctional; their ability to secrete interferon gamma and tumor necrosis factor α correlated with early expression of CD127 but not PD-1. Based on a comparison of vaccine-induced and infection-induced T cells from the same chimpanzee, the CD127(+) memory precursor phenotype was induced by the vaccine itself rather than by low viremia. In contrast, induction of PD-1 correlated with viremia, and levels of intrahepatic PD-1, PD-L1, and 2,5-OAS-1 messenger RNAs correlated with peak titers of HCV.


CONCLUSIONS
Compared with infection, vaccination-induced HCV-specific CD127(+) T cells with high functionality that persisted at higher levels for a longer time. Control of viremia prevented up-regulation of PD-1 on T cells and induction of PD-1, PD-L1, and 2,5-OAS-1 in the liver. Early development of a memory T-cell phenotype and, via control of viremia, attenuation of the inhibitory PD1-PD-L1 pathway might be necessary components of successful vaccine-induced protection against HCV.
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Su-Hyung
SH
Park
Eui-Cheol
EC
Shin
Stefania
S
Capone
Laura
L
Caggiari
Valli
V
De Re
Alfredo
A
Nicosia
Antonella
A
Folgori
Barbara
B
Rehermann
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004279:DNA, Viral / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D002679:Pan troglodytes; D010641:Phenotype; D054504:Precursor Cells, T-Lymphoid / Q000187:drug effects* / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014611:Vaccination; D014761:Viral Hepatitis Vaccines / Q000276:immunology* / Q000494:pharmacology; D019562:Viral Load
D060890:B7-H1 Antigen; D004279:DNA, Viral; D053699:Interleukin-7 Receptor alpha Subunit; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014761:Viral Hepatitis Vaccines; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase