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 characterized. 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.

Action is invigorated in the presence of reward-predicting stimuli and inhibited in the presence of punishment-predicting stimuli. Although valuable as a heuristic, this Pavlovian bias can also lead to maladaptive behaviour and is implicated in addiction. Here we explore whether Pavlovian bias can be overcome through training. Across five experiments, we find that Pavlovian bias is resistant to unlearning under most task configurations. However, we demonstrate that when subjects engage in instrumental learning in a verbal semantic space, as opposed to a motoric space, not only do they exhibit the typical Pavlovian bias, but this Pavlovian bias diminishes with training. Our results suggest that learning within the semantic space is necessary, but not sufficient, for subjects to unlearn their Pavlovian bias, and that other task features, such as gamification and spaced stimulus presentation may also be necessary. In summary, we show that Pavlovian bias, whilst robust, is susceptible to change with experience, but only under specific environmental conditions.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses plasticity by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces this microglia-dependent inhibitory plasticity by promoting synaptic enrichment of GABAARs. We further show that in turn, microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunts sleep-dependent memory consolidation. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of inhibitory synapses, ultimately sculpting sleep slow waves and memory.