Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches.
Animals
Cytokines
/ metabolism
Hepatitis B Surface Antigens
/ blood
Hepatitis B virus
/ immunology
Hepatitis B, Chronic
/ blood
Humans
Immune Checkpoint Inhibitors
/ therapeutic use
Immunotherapy, Adoptive
/ methods
Killer Cells, Natural
/ immunology
Lymphocyte Activation
Mice
RNAi Therapeutics
/ methods
T-Lymphocytes, Regulatory
/ immunology
T cell exhaustion
chronic HBV infection
immune-therapy
immunoregulatory mechanisms
liver environment
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
12
11
2019
accepted:
14
04
2020
entrez:
2
6
2020
pubmed:
2
6
2020
medline:
1
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32477347
doi: 10.3389/fimmu.2020.00849
pmc: PMC7235343
doi:
Substances chimiques
Cytokines
0
Hepatitis B Surface Antigens
0
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
849Informations de copyright
Copyright © 2020 Fisicaro, Barili, Rossi, Montali, Vecchi, Acerbi, Laccabue, Zecca, Penna, Missale, Ferrari and Boni.
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