TY - JOUR 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 DO - 10.1136/gutjnl-2018-316641 SP - gutjnl-2018-316641 AU - Anita Schuch AU - Elahe Salimi Alizei AU - Kathrin Heim AU - Dominik Wieland AU - Michael Muthamia Kiraithe AU - Janine Kemming AU - Sian Llewellyn-Lacey AU - Özlem Sogukpinar AU - Yi Ni AU - Stephan Urban AU - Peter Zimmermann AU - Michael Nassal AU - Florian Emmerich AU - David A Price AU - Bertram Bengsch AU - Hendrik Luxenburger AU - Christoph Neumann-Haefelin AU - Maike Hofmann AU - Robert Thimme Y1 - 2019/01/08 UR - http://gut.bmj.com/content/early/2019/01/08/gutjnl-2018-316641.abstract N2 - 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. ER -