Abstract A significant proportion of individuals infected by HBV develops chronic infection. Antiviral effectors such as Natural Killer (NK) cells have impaired functions in these patients, but the molecular mechanism responsible for this dysfunction remains poorly characterized. Here, we show that peripheral NK cells from chronic hepatitis B (CHB) patients have a defective capacity to produce IFN-γ, MIP1-β and TNF-α but retain an intact killing capacity. This functional phenotype was associated with a decrease in the expression of NKp30 and CD16, combined with defects in IL-15 stimulation of the mTOR pathway. Transcriptome analysis of NK cells in CHB patients further revealed a strong enrichment for transcripts typically expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion rely on common molecular mechanisms. In particular, the transcription factor thymocyte selection-associated HMG box protein (TOX) and several of its targets, including immune checkpoints, were over-expressed in NK cells of CHB patients. This T cell exhaustion signature was predicted to be dependent on the calcium (Ca 2+ )-associated transcription factor NFAT. In line with this, when stimulating the Ca 2+ -dependent pathway in isolation, we recapitulated the dysfunctional phenotype. Thus, deregulated Ca 2+ signalling could be a central event in both T cell exhaustion and NK cell dysfunction that occur during chronic infections.

Peripheral Natural Killer cells from chronic hepatitis B patients display molecular hallmarks of T cell exhaustion