Abstract
Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications.
Highlights
About 250 milion people worldwide are chronically infected with hepatitis B virus (HBV)
Natural Killer (NK) cells have been considered as part of the innate arm of the immune response, which belong to the family of innate lymphoid cells (ILC), since they do not express receptors encoded by rearranging genes [6]
Compared with conventional FcεRIγ+CD56dim NK cells, this NK subpopulation displays different metabolic properties, including a higher fraction of functional, polarized mitochondria, and a stable epigenetic signature, along with increased CD16-mediated degranulation potential, which skews the whole NK cell population toward a higher CD16 sensitivity with enhanced antibody-dependent cell cytotoxicity (ADCC). These data show the mutual influence of HBVand HCMV-persisting infections on the NK cell repertoire, which significantly affects the immune response to chronic HBV infection, and point to the usefulness of HCMV co-infection evaluation in the application of immunotherapeutic approaches targeting NK cells for an HBV cure [49]
Summary
About 250 milion people worldwide are chronically infected with hepatitis B virus (HBV). Attacking healthy cells is prevented thanks to the recognition of HLA-class I molecules by specific inhibitory receptors [12], which are represented by members of the killer immunogobulin-like receptors KIR/CD158 family, LIR-1, and the CD94/NKG2A heterodimer. The latter is typical of an earlier NK cell maturation stage than KIRs, with KIRs-NKG2A co-expression detectable only on a subset of maturing cells [12,13]. Down-regulation of activating receptors and up-regulation of inhibitory receptors have been reported as the prevalent NK cell phenotypic signature in tumors and chronic infections, which results in impaired effector functions that may contribute to viral persistence and tumor growth [15]
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