Impact Of Hepatitis B Virus On Natural Killer Cell Activity

Marie MAROTEL, Centre de Recherche en Infectiologie, France
ROBLOT G. 1 , ZANNETTI C. 2 , ROCHEFORT P. 3 , AINOUZE M. 1 , TOUT I. 1 , CHARRIER E. 1,4 , BESSON L. 1,4 , MARÇAIS A. 1 , WALZER T. 1 , HASAN U. 1

1 INSERM U1111, Centre de Recherche en Infectiologie, Lyon, France
2 Consultys, Lyon, France
3 Centre Léon Bérard, Lyon, France
4 Hospices civiles de Lyon (HCL), Lyon, France

Natural killer (NK) cells play a crucial role in the immunosurveillance of cancers and in the early control of viral infections. However, in the context of chronic infections, e.g HCV or HIV infections, a state of NK cell tolerance or exhaustion has been reported. IL-15 induced-mTOR activation is essential for NK cell activation and acquisition of effector functions. In addition, the immunosuppressive cytokine TGF-b can impede NK cell control of metastatic development and disrupts mTOR activation by IL-15 (unpublished results). We therefore hypothesized that NK cell exhaustion might result from mTOR pathway deregulation caused by viruses.

Using the oncovirus Hepatitis B virus (HBV) as liver chronic infection model, we studied the regulation of IL-15 and TGF-β. Both peripheral (blood) and local (liver) crosstalk between macrophages and NK cells were investigated. Kupffer Cells (KC), (i.e specialized liver macrophages) transcriptome was also characterized in this context.
Our data show that IL-15 levels dropped in human KC as well as in monocytes exposed to HBV at a viral genome equivalent of 1000 while TGF-β1 levels increased. This was further confirmed at the protein level. Moreover, by co-cultured experiments with monocytes, we observed that HBV can inhibit IL-15 signaling as read out by pS6 (mTOR activation marker) and impaired NK cells functionality (read out: Granzyme B/perforin).

In conclusion, we highlighted a putative mechanism by which HBV could alter innate NK cell response. The virus may increase TGF-b1 secretion that has immune-modulatory properties and down regulate IL-15 expression and signaling leading to the impairment of NK cells activity. This process might participate to NK cells exhaustion during chronic infection. Further studies focusing on the mechanistic used by HBV are required. Such knowledge may have important clinical implications to develop novel immunotherapeutic approaches.

This study was supported by La Ligue contre le Cancer and l’ANRS.