PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

Abstract

24Programmed death ligand 1 (PD-L1) has been recently shown to be a major 25 obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) 26 on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely 27 used to treat hepatitis B virus(HBV)infection, but its antiviral effect vary greatly 28 and the mechanism is not totally clear. We found that IFN-α/γ induced a marked 29 increase of PD-L1 expression in hepatocytes. Signal and activators of transcription 30 ( Stat1) was then identified as a major transcription factor involved in 31 IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the 32 PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell 33 activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in 34 HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an 35 important role in mediating T cell hyporesponsiveness and inactivating 36 liver-infiltrating T cells in the hepatic microenvironment. These data raise further 37 potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic 38 vaccines. 39 40 42 hepatitis B virus (HBV). Ultimate HBV clearance requires the coordination of the 43 potent T cell immune response and effective humoral immunity. However, -3 -44 HBV-specific T cell response, which plays a vital role in HBV clearance, is severely 45 impaired in chronic hepatitis B (CHB) patients, leading to long-term immune 46 tolerance [1, 2]. Several mechanisms may contribute to HBV-specific T cell tolerance 47 and exhaustion, including upregulation of co-inhibitory molecules such as 48 programmed death 1 (PD-1), T-cell immunoglobulin and mucin domain-49 containing molecule 3 (TIM-3), T-cell immunoglobulin and ITIM domain 50 (TIGIT), lymphocyte-activation gene 3 (LAG3), immunosuppressive prostaglandin 51 E2 (PGE2) receptors, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and proapoptotic 52 protein Bcl2-interacting mediator (Bim) on HBV-specific CD8 + T cells, as well as on 53 CD4+ T cells and NK cells. [3-5]. Additionally, regulatory T cells and suppressive 54 cytokines also contribute to virus-specific T cell failure [6]. 55 Among the co-expressed inhibitory receptors on T cells, programmed death 56 ligand 1 (PD-L1) plays a critical role in impaired T cell immune responses. Of note, 57 its ligand PD-L1, a 40 kDa transmembrane protein, is constitutively expressed on 58 liver DCs, Kupffer cells, stellate cells, liver sinusoidal endothelial cells, and 59 hepatocytes. Binding of PD-L1 to PD-1 leads to T cell dysfunction by inhibiting T 60 cell activation, causing T cell exhaustion, anergy, and T cell apoptosis, as well as by 61 inducing Treg differentiation [7-11]. In addition, elevated PD-L1 levels in liver were 62 observed in chronic necroinflammatory liver diseases and autoimmune hepatitis [12, 63 13]. These indicate the immune regulatory function of the liver microenvironment that 64 may lead to T cell tolerance. 65 As an first-line treatment option, ...

Identifying potential biomarkers in hepatitis B virus infection and its response to the antiviral therapy by integrated bioinformatic analysis

“…Finally, STAT1, a key component in IFN signalling pathways and its upstream IFN/Janus kinase (JAK)/STAT signalling pathway, has also piqued interest in previous studies showing that HBV can influence the IFN/JAK/STAT signalling pathway and the differential phosphorylation of STAT1. Through STAT1‐related pathways, HBV infection not only induced monocytes to express lower levels of IFN signalling/stimulated genes and higher levels of IL‐10, 32 but also led to the suppression of the anti‐HBV T cell response 33,34 . A specific enhancer of STAT1, 2‐NP, rescued IFN signalling in HBV‐infected monocytes, 32 which corroborate our findings that a higher level of STAT1 is found in responders.…”

“…31 Based on previous studies and our findings, lower expression of pre-treatment infection not only induced monocytes to express lower levels of IFN signalling/stimulated genes and higher levels of IL-10, 32 but also led to the suppression of the anti-HBV T cell response. 33,34 A specific enhancer of STAT1, 2-NP, rescued IFN signalling in HBV-infected monocytes, 32 which corroborate our findings that a higher level of STAT1 is found in responders. More studies on the regulatory mechanism of IFN/JAK/STAT signalling may help elucidate the mechanism of persistent HBV infection and the poor response rates to antiviral therapy in CHB patients.…”