BaCKgRoUND aND aIMS: Natural killer (NK) cells play a crucial role in the clearance of human viruses but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). Cooperation with dendritic cells (DCs) is pivotal for obtaining optimal NK cell antiviral function; thus, we investigated whether HBV might impact the ability of DCs to sustain NK cell functions. appRoaCH aND ReSUltS: Human DCs were poor stimulators of interferon-gamma (IFNγ) production by NK cells when exposed to HBV, while maintaining the capability to trigger NK cell cytotoxicity. HBV prevented DC maturation but did not affect their expression of human leukocyte antigen class I, thus allowing DCs to evade NK cell lysis. Tolerogenic features of DCs exposed to HBV were further supported by their increased expression of IL-10 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase, which contributed to the impairment of DC-mediated NK cell IFNγ production and proliferation, respectively. HBV could also inhibit the expression of inducible immunoproteasome (iP) subunits on DCs. In fact, NK cells could induce iP subunit expression on DCs, but they failed in the presence of HBV. Remarkably, circulating blood DC antigen1 (BDCA1) + DCs isolated from patients with CHB were functionally compromised, hence altering, in turn, NK cell responses. CoNClUSIoNS:The abnormal NK-DC interplay caused by HBV may significantly impair the efficacy of antiviral immune response in patients with CHB. (Hepatology 2021;74:550-565). HBV is a major cause of inflammatory liver disease of variable severity that affects millions of people worldwide. Despite the availability of vaccine, more than 257 million people are still infected with HBV. (1) The pathophysiology of HBV infection is complex and closely linked to host immune response. An ineffective and weak immune response toward HBV is thought to be the fundamental underlying cause for evolution of HBV infection until the establishment of chronic disease. (2,3) Progression of persistent infection together with cell death and regeneration of infected hepatocytes succeed one another, leading to chronic inflammation and fibrosis often associated with the risk of developing liver cirrhosis and hepatocellular carcinoma. (4)

Natural killer (NK) cells represent innate effector cells potentially able to play a role during the immune response against multiple myeloma (MM). To better define the distribution and the specific properties of NK cell subsets during MM disease, we analyzed their features in the bone marrow and peripheral blood of newly diagnosed MM patients. Our findings revealed that, in both compartments, NK cells were more abundant than in healthy donors. Among total MM-NK cells, a significant increase of CD94lowCD56dim NK cell subset was observed, which already appears in clinical precursor conditions leading to MM, namely monoclonal gammopathy of undetermined significance and smoldering MM, and eventually accumulates with disease progression. Moreover, a consistent fraction of CD94lowCD56dim NK cells was in a proliferation phase. When analyzed for their killing abilities, they represented the main cytotoxic NK cell subset against autologous MM cells. In vitro, MM cells could rapidly induce the expansion of the CD94lowCD56dim NK cell subset, thus reminiscent of that observed in MM patients. Mechanistically, this accumulation relied on cell to cell contacts between MM and NK cells and required both activation via DNAM-1 and homophilic interaction with CD56 expressed on MM cells. Considering the growing variety of combination treatments aimed at enhancing NK cell-mediated cytotoxicity against MM, these results may also be informative for optimizing current immunotherapeutic approaches.

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Human CD117+CRTH2neg innate lymphoid cells (ILC) comprise multipotent precursors (ILCp), which are able to differentiate into subtypes in response to different signals received in peripheral tissues. NKp46+ ILCp have been reported to associate with ILC3 whereas KLRG1+ILCp with ILC2, although the latter can also generate other ILC subsets, thus, maintaining a substantial plasticity. We here showed that CD62L is expressed by ILCp exclusively within KLRG1+ population and its expression marks a loss of their broad differentiation potential. Analysis of cytokine production and relevant markers demonstrated that CD62L+ILCp mainly differentiate into ILC2 whereas CD62Lneg counterpart can also differentiate into other ILC subsets depending on the signals they receive. Remarkably, in peripheral blood of psoriatic patients, where ILC3 are usually enriched, CD62L+ILC were drastically reduced, whereas CD62LnegILC2 upregulated both RORγt and NKp46, thus, suggesting an ongoing conversion to ILC3. Therefore, CD62L now emerges as a potential marker to identify a skewing toward type 2 among ILCp.

Proinflammatory monocytes play a preponderant role in the development of a cytokine storm causing fatal consequences in coronavirus disease 2019 (COVID-19) patients, highlighting the importance of analyzing in more detail monocyte distribution in these patients. In this study, we identified an atypical monocyte subpopulation expressing CD56 molecules that showed a low level of HLA-DR and high level of l-selectin. They released higher amounts of TNF-α and IL-6 and expressed genes associated with an excessive inflammatory process. Remarkably, the frequency of CD56+ monocytes inversely correlated with that of CD16+ monocytes and a high CD56+/CD16+monocyte ratio was associated with both disease severity and mortality, as well as with serum concentration of type I IFN, a factor able to induce the appearance of CD56+ monocytes. In conclusion, severe COVID-19 is characterized by the abundance of hyperinflammatory CD56+ monocytes, which could represent a novel marker with prognostic significance and, possibly, a therapeutic target for controlling the inflammatory process occurring during COVID-19.