NK cells are emerging as potent regulators of adaptive immunity in virus infection. Our group recently documented the partially TRAIL-dependent deletion of HBV-specific T cells by NK cells. For this study, we investigated the underlying interactions between NK cells and T cells through the NKG2D pathway in chronic HBV infection. In this study, we observed that activated and HBV-specific T cells, especially the CD4 fraction, expressed NKG2D ligands (NKG2D-L) not normally seen on T cells. NKG2D-L upregulation was further enriched on CD4 T cells in HBV-infected livers compared to the circulation and control livers. Oxidative stress, one noteworthy pathogenic feature of HBV infection, was demonstrated to recapitulate the T cell NKG2D-L upregulation pattern seen in patients with chronic hepatitis B (CHB). NK cells from patients with CHB maintained NKG2D expression and their increased activation and cytotoxicity could be driven by NKG2D-L expressing cells. In line with the distinctive features of T cells and NK cells in CHB, we discovered a positive correlation between activation of NKG2D+NK cells and the NKG2D-L (MICA/B) levels on CD4 T cells. Additionally, the pro-inflammatory cytokine IFN-α, used in HBV treatment, was shown to favour for NKG2D-mediated regulation. To conclude, we provide the first ex vivo evidence that human T cells, particularly those sequestered within tissues, can become visible to the stress surveillance system by the induction of NKG2D-L. We show that in active CHB, T cells upregulate NKG2D-L which can drive NK cell activation and cytotoxicity via the NKG2D pathway. These interactions may be triggered by aberrant oxidative stress and result in a homeostatic response of "damage removal", thereby limiting T cell antiviral immunity. Therefore, efforts to manipulate the HBV-infected liver milieu in order to decrease T cell oxidative stress and diminish constraints from NK cells and the NKG2D pathway should be considered to reduce HBV pathogenesis and promote immunity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:746193 |
| Date | January 2016 |
| Creators | Huang, W. C. |
| Contributors | Maini, M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1496146/ |
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