T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System

Abstract

NK cells, which are highly enriched in the liver, are potent regulators of antiviral T cells and immunopathology in persistent viral infection. We investigated the role of the NKG2D axis in T cell/NK cell interactions in hepatitis B. Activated and hepatitis B virus (HBV)–specific T cells, particularly the CD4 fraction, expressed NKG2D ligands (NKG2DL), which were not found on T cells from healthy controls (p < 0.001). NKG2DL-expressing T cells were strikingly enriched within HBV-infected livers compared with the periphery or to healthy livers (p < 0.001). NKG2D+NK cells were also increased and preferentially activated in the HBV-infected liver (p < 0.001), in direct proportion to the percentage of MICA/B-expressing CD4 T cells colocated within freshly isolated liver tissue (p < 0.001). This suggests that NKG2DL induced on T cells within a diseased organ can calibrate NKG2D-dependent activation of local NK cells; furthermore, NKG2D blockade could rescue HBV-specific and MICA/B-expressing T cells from HBV-infected livers. To our knowledge, this is the first ex vivo demonstration that non-virally infected human T cells can express NKG2DL, with implications for stress surveillance by the large number of NKG2D-expressing NK cells sequestered in the liver.

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

“…40 In contrast, silencing NKG2D and DAP10 can reduce the cytotoxcity of T and NK cell, 41 and NKG2D dysfunction impairs anti-tumor activities of memory CD8 + T cell. 42 Besides, activation of NKG2D and DAP10 also enhance the inflammatory cytokine production by murine CD8 + T cells as reported previousl, 43,44 and NKG2D signaling are also able to promote T cell infiltration and accumulation in tumors and live, 45,46 which are consistent with our in vivo results obtained from lung cancer PDX mouse model.…”

Immune function of plasmacytoid dendritic cells, natural killer cells, and their crosstalk in HBV infection

“…Perhaps, the stressed environment of the HBV infected liver might upregulate expression of NKG2DL MICA/B on virus‐specific CD4 T cells within the HBV‐infected liver milieu, which can drive NKG2D‐dependent activation of local NK cells and makes those T cells susceptible to deletion by NK cells. NKG2D blockade can rescue HBV‐specific and MICA/B‐expressing CD4+ T cells from HBV‐infected livers (Figure ).…”

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics

“…A robust antiviral NK cell response is important for cytolysis of HBV infected hepatocytes; however, NK cells also have a regulatory role, causing deletion of HBV‐specific T cells when in close contact . The interaction of TRAIL+ and NKG2D+ NK cells with T cells expressing the receptor, TRAIL‐R2 and/or NKG2D ligands leads to T cell apoptosis, which, in vitro, can be partially prevented by blockade of these pathways . The data on whether the phenotype of NK cells is altered, with viral load reduction, are limited.…”

“…82 The interaction of TRAIL+ and NKG2D+ NK cells with T cells expressing the receptor, TRAIL-R2 and/or NKG2D ligands leads to T cell apoptosis, which, in vitro, can be partially prevented by blockade of these pathways. 82,83 The data on whether the phenotype of NK cells is altered, with viral load reduction, are limited. A recent report demonstrated an inverse correlation with an "activatory" NK cell phenotype (HLA-DR+, CD38+, Ki67+, TRAIL+, NKG2D+) and the proportion of HBV-specific T cells in patients undergoing NA therapy.…”