Abstract
BackgroundChemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear.MethodsWe assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation.ResultsFrom in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed.ConclusionsFindings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.
Highlights
250 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at high risk of developing liver steatosis, cirrhosis, end-stage liver failure or hepatocellular carcinoma [1, 2]
Since CCL19 appears to trigger antigen-presenting cells (APCs) and T-cell trafficking, we evaluated its possible roles in enhancing CD8? T-cell function in HBV-infected patients and elucidated its possible functions and mechanisms in promoting HBV clearance
Our results showed that CCL19mediated hepatitis B core (HBc) primary and restimulated Peripheral blood mononuclear cells (PBMCs) to produce higher level of IFN-c in supernatants, whereas this enhanced effect was partially decreased by chemokinereceptor type 7 (CCR7) knockdown and CCR7 monoclonal Ab even though adding CCL19 protein and completely abrogated by phosphoinositide 3-kinase (PI3K) signal inhibitor LY294002
Summary
250 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at high risk of developing liver steatosis, cirrhosis, end-stage liver failure or hepatocellular carcinoma [1, 2]. CCL19 is the only chemokine known to effectively stimulate b-arrestin-mediated CCR7 phosphorylation and internalization, which results in receptor desensitization and antigen (Ag)-presenting DC migration [13], thereby affecting T-cell responses. HBx functions downstream of the chemokine-receptor axis, limiting the apoptotic response and resulting in chronic HBV infection [14]. Studies on CCR7 signaling and its influence on viral pathogenesis have elucidated the complex interplay among viruses, target cells and host immune responses, especially with respect to how changes in the number of CCR7-positive cells during chronic infection and latency promote viral invasion, e.g., HIV-1 [15,16,17], influenza virus [18, 19], dengue virus (DENV) [20,21,22], respiratory syncytial virus (RSV) [23,24,25], etc. Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Whether HBV can be cleared by CCL19activated immunity remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
