부산대학교 도서관

Background T-cell exhaustion seems to play a critical role in CD8.sup.+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4.sup.+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4.sup.+ T-cell failure. Methods The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4.sup.+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4.sup.+ T-cell proliferation and cytokine production. Results CD4.sup.+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer.sup.+ CD4.sup.+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-[gamma], IL-2 and TNF-[alpha] secretion as well as enhanced CD4.sup.+ T-cell expansion almost in treated patients with viral control. Conclusion HBV-specific CD4.sup.+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4.sup.+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4.sup.+ T-cell functionality with heterogeneous patterns of CD4.sup.+ T-cell rejunivation.
Author(s): Bijan Raziorrouh [sup.1] [sup.*] , Malte Heeg [sup.1] [sup.2] , Peter Kurktschiev [sup.1] , Winfried Schraut [sup.1] , Reinhart Zachoval [sup.1] , Clemens Wendtner [sup.4] , Martin Wächtler [sup.4] [...]