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PD ‐1/ PDL 1 and CD 28/ CD 80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication
Author(s) -
Wang X. F.,
Lei Y.,
Chen M.,
Chen C. B.,
Ren H.,
Shi T. D.
Publication year - 2013
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12061
Subject(s) - cd80 , natural killer t cell , cd86 , cd28 , microbiology and biotechnology , hepatitis b virus , immunology , interferon , peripheral blood mononuclear cell , genetically modified mouse , t cell , chemistry , biology , transgene , immune system , cd40 , cytotoxic t cell , virus , biochemistry , in vitro , gene
Summary α‐Galactosylceramide (α‐ G al C er)‐activated natural killer T ( NKT ) cells have antiviral properties against hepatitis B virus ( HBV ). However, α‐GalCer activation of NKT cells can induce anergy. We hypothesized that this effect may be overcome by a treatment strategy that includes manipulation of CD 28/ CD 80 costimulatory and PD ‐1/ PDL 1 coinhibitory signals of NKT cells, thereby enhancing the anti‐ HBV effect of α‐ G al C er. We established a transgenic mouse model of chronic HBV infection and investigated hepatic NKT cell frequencies, functions and expression of immunomodulatory factors. Our results showed that compared with uninfected control mice, hepatic NKT cells from HBV transgenic mice displayed lower frequencies (7.91% vs 16.74%, P < 0.05), impaired capabilities to produce interferon ( IFN )‐γ (5.6% vs 1.4%, P < 0.05) and interleukin ( IL )‐4 (6.8% vs 0.3%, P < 0.05), higher expression of PD ‐1 (9.64% vs 6.36%, P < 0.05) and lower expression of CD 28 (5.05% vs 28.88%, P < 0.05). However, when hepatic mononuclear cells ( MNC s) were isolated from HBV transgenic mice, α‐GalCer exposure in culture remarkably upregulated both PD ‐1 + NKT cells ( P < 0.05) and CD 28 + NKT cells ( P < 0.05). Furthermore, when HBV transgenic mice were treated with combination therapies consisting of α‐GalCer and anti‐PDL1 monoclonal antibody (mAb) and/or anti‐ CD 80/anti‐ CD 28 mAbs, IFN ‐γ + NKT cell frequency was selectively increased ( P < 0.05) and HBV replication was suppressed; these effects were accompanied by varying degrees and types of liver damage. Surprisingly, activating CD28/CD80 signal in HBV transgenic mice was more effective but caused less liver injury than blocking PD ‐1/ PDL 1 signal in modulating αGalCer‐activated NKT cell function to inhibit HBV infection. Our findings also show that combined therapy with blocking PD ‐1/ PDL 1 and activating CD 28/ CD 80 signal in the presence of aG alCer cannot superimpose the effect of antivirus. α‐ G al C er combination therapy that modulates the CD 28/ CD 80 pathways of NKT cells may represent a promising approach to inhibit HBV replication in chronically infected patients.