RT Journal Article
SR Electronic
T1 Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 905
OP 915
DO 10.1136/gutjnl-2018-316641
VO 68
IS 5
A1 Schuch, Anita
A1 Salimi Alizei, Elahe
A1 Heim, Kathrin
A1 Wieland, Dominik
A1 Kiraithe, Michael Muthamia
A1 Kemming, Janine
A1 Llewellyn-Lacey, Sian
A1 Sogukpinar, Özlem
A1 Ni, Yi
A1 Urban, Stephan
A1 Zimmermann, Peter
A1 Nassal, Michael
A1 Emmerich, Florian
A1 Price, David A
A1 Bengsch, Bertram
A1 Luxenburger, Hendrik
A1 Neumann-Haefelin, Christoph
A1 Hofmann, Maike
A1 Thimme, Robert
YR 2019
UL http://gut.bmj.com/content/68/5/905.abstract
AB Objective A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion.Design By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses.Results HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression.Conclusions Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.