2. Academic Validation
  3. CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

  • J Gastroenterol. 2021 Aug;56(8):769-785. doi: 10.1007/s00535-021-01799-8.
Yan Yan 1 2,  Wei Zhao 3,  Wei Liu 3,  Yan Li 3,  Xu Wang 4,  Jingna Xun 5,  Chantsalmaa Davgadorj 4
Affiliations

Affiliations

  • 1 Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China. [email protected].
  • 2 Hepatology Institute of Wuxi, The Fifth People's Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China. [email protected].
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China.
  • 4 Laboratory for Infection and Immunity, The Fifth People's Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China.
  • 5 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
PMID: 34218330 DOI: 10.1007/s00535-021-01799-8
Abstract

Background: Chemokine (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.

Methods: We 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.

Results: From 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.

Conclusions: Findings 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.

Keywords

Apoptosis; CD8+ T cell; Chemokine (C–C motif) ligand 19 (CCL19); Hepatitis B virus; Regulatory T cell (Treg cell).

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