Abstract
A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.
Highlights
Chronic HBV infections remain a major public health problem worldwide [1]
Even when CD8 T cell priming occurred within a liver environment where HBV core antigen expression, induced by injection with a low dose of a hepatotropic adeno-associated viral vector (AAV) encoding the HBV core protein, was limited to less than 5% of hepatocytes, effector differentiation was not supported despite much lower levels of antigen expression [74]
In addition to hepatic stellate cells (HSCs), Kupffer cells (KCs), and macrophages, the liver is enriched in populations of regulatory cells, such as myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), that can promote tolerance by producing immunosuppressive cytokines (IL-10 and TGF-β) and by expressing high levels of coinhibitory ligands, such as PD-L1 and Galectin-9 (Figures 2A,B)
Summary
Chronic HBV infections remain a major public health problem worldwide [1]. Currently, there are no curative treatments and available therapies are effective in inhibiting HBV replication, but are of limited efficacy on cccDNA and HBsAg concentrations, thereby requiring long-lasting administrations to avoid the risk of HBV reactivation at withdrawal [2,3,4]. A much simpler possibility, which is being explored in different laboratories, consists in the use of phenotypic panels, including exhaustion and memory molecules, to study total, unfractionated T cells, in view of data indicating that exhaustion can partially affect the overall CD4 and CD8 T cell populations In this regard, the downregulation of CD3ζ and CD28 has been associated to functional defects in total non-antigen-specific CD8 T cells in vitro and in vivo in CHB patients with high viral load [55]. In view of the multifactorial nature of T cell exhaustion pathogenesis in HBV infection, the possibility to reconstitute T cell functionality with a single intervention selectively focused on immune check-points seems to be highly unlikely This conclusion is further reinforced by the recent finding that PD-1 blockade doesn’t allow complete correction of the specific epigenetic profiles which are associated with CD8 T cell exhaustion [65, 66]. The lack of an epigenetic effect provides the rationale for combining checkpoint blockade with epigenetic drugs, a therapeutic strategy already tested in the setting of anti-tumor immunotherapy
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