Abstract
Antiviral effectors such as natural killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterised. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.
Highlights
Hepatitis B Virus (HBV) infection results in immune mediated viral clearance in 90-95%of adults
Similar to previously described cohorts, a higher proportion of chronic hepatitis B (CHB) patients than healthy donors (HD) were seropositive for HCMV (Table 1 and Supplemental Figure 1A), a characteristic that led to higher representation of the adaptive NKG2C+ subset in the Natural Killer (NK) cell population (Supplemental Figure 1B)
We explored the impact of CHB on peripheral NK cell function and phenotype and uncovered a profound convergence in the transcriptional mechanisms governing T cell exhaustion and NK cell dysfunction
Summary
Hepatitis B Virus (HBV) infection results in immune mediated viral clearance in 90-95%of adults. Hepatitis B Virus (HBV) infection results in immune mediated viral clearance in 90-95%. The remaining 5-10% fail to control viral infection due to failure in type 1 cellular immunity leading to chronic hepatitis B (CHB)[1]. NK cells from CHB patients are characterized by a decreased capacity to produce cytokines such as IFN-γ and TNF-α despite maintaining or even increasing their cytotoxic capacity[9,10,11,12]. This phenomenon has been termed “functional dichotomy”[9]. In HBV infected patients, this balance might be skewed as a decrease in the expression of several activating receptors was previously observed in patient’s NK cells[7,11,12,14]
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