Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C
Abstract
:1. Introduction
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- innate immunity receptors
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- co-inhibitory molecules
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- metabolic pathways
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- cytokine functions
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- epigenetic control of DNA transcription
2. Stimulation of Innate Immunity Receptors as an Immunomodulatory Strategy to Overcome HBV-Specific T Cell Exhaustion
3. Boosting Adaptive Immune Response by Blocking Co-Inhibitory Pathways
4. Targeting Metabolism to Restore T Cell Exhaustion
4.1. Early Chronic Infections
4.2. Established Chronic Infections
5. Cytokine Fueling for T Cell Restoration
6. T Cell Epigenetic Targets for Therapies during Chronic Infections
7. Future Perspectives
Funding
Conflicts of Interest
References
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Immune-Modulatory Interventions | Class of Agents | HBV | HCV |
---|---|---|---|
Stimulation of innate immunity receptors | GS-9620 | [31,32,33,34] | - |
APR002 | [35,36] | - | |
GS-9688/selgantolimod | [37,38,39,40] | - | |
R848 | [41] | - | |
CL413 | [41] | - | |
AIC649 | [42] | - | |
SB 9200 | [43] | [44] | |
Co-inhibitory pathways blocking | PD-1 | [45,46,47,48,49,50,51,52,53] | [45] |
CTLA-4 | [54] | - | |
TIM-3 | [55] | - | |
2B4 | [56] | - | |
Co-stimulatory signaling activation | CD137 | [45] | [45] |
OX40 | [45,57] | [45] | |
Cytokine fueling | IL-15 | [58] | - |
IL-12 | [59,60] | - | |
IL-2 | [61] | - | |
IL-7 | - | [62] | |
PGE2 inhibition | [63] | - | |
Metabolic modulation | p53, p38, AMPK, ATM inhibitory compounds | - | [64] |
N-acetyl-L-cysteine (NAC) | - | [64] | |
MitoQ/MitoTempo | [65,66] | [67] | |
Polyphenols Resveratrol and Oleuropein | [65,66] | - | |
Arginine replenishment | [68] | - | |
Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor | [69] | - | |
Epigenetic intervention | Histone methyltransferses inhibitors | - | [64] |
Class of Agents | In Vitro/ In Vivo Use | Mechanism of Action | Target Cells | Disease | References |
---|---|---|---|---|---|
GS-9620 | In vivo | Induction of TLR7 activation | - | HBV | [31,32,33,34] |
APR002 | In vivo | Induction of TLR7 activation | - | HBV | [35,36] |
GS-9688/selgantolimod | In vitro/ In vivo | Agonist of endosomal TLR8 | Liver resident cells (activated DCs, mononuclear phagocytes and immune cells) | HBV | [37,38,39,40] |
R848 | In vitro | Dual-acting TLR7/8 agonist | Hepatocytes | HBV | [41] |
CL413 | In vitro | Dual-acting TLR2/7 agonist | Hepatocytes | HBV | [41] |
AIC649 | In vivo | TLR9 pathway activator | - | HBV | [42] |
SB 9200 | In vivo | RIG-I agonist | - | HBV, HCV | [43,44] |
Checkpoint blockade | In vitro | PD-1, CTLA-4, TIM-3 and 2B4 | T cells | HBV, HCV | [45,46,47,53,54,55,56] |
CD137 and OX40 | In vitro | Co-stimulatory CD137 or OX40 signaling activation | T cells | HBV, HCV | [45,57] |
Nivolumab | In vivo | Anti-PD-1 for PD-1/PD-L1 blockade | T cells | HBV | [48,49,50,51,52,70] |
p53, p38, AMPK, ATM inhibitory compounds | In vitro | Stress-sensor signaling kinase blockade | T cells | HCV | [64] |
N-acetyl-L-cysteine (NAC) | In vitro | Anti-oxidant compounds | T cells | HCV | [64] |
MitoQ/MitoTempo | In vitro/ In vivo | Mitochondrial anti-oxidant treatment | T cells | HBV, HCV | [65,66,67] |
Polyphenols Resveratrol and Oleuropein | In vitro | Mitochondrial function and intracellular proteostasis restoration | T cells | HBV | [65,66] |
Histone methyltransferses inhibitors | In vitro | EZH2 and G9a blockade | T cells | HCV | [64] |
Arginine | In vitro | Arginine replenishment | T cells | HBV | [68] |
acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor | In vitro | Inhibition of cholesterol esterification | T cells | HBV | [69] |
IL-15 | In vitro | Cellular proteostasis and mitochondrial function restoration | T cells | HBV | [58] |
IL-12 | In vitro | Reverse mitochondria depolarization and glycolysis dependence | T cells | HBV | [59,60] |
IL-2 | In vitro/ In vivo | T cell proliferate and differentiation restoration | T cells | HBV | [61] |
IL-7 | In vitro | Exhaustion characterization and TRAF1 restoration | T cells | HCV | [62] |
PGE2 inhibition | In vitro | PGE2 inhibitory signaling blockade | T cells | HBV | [63] |
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Barili, V.; Vecchi, A.; Rossi, M.; Montali, I.; Tiezzi, C.; Penna, A.; Laccabue, D.; Missale, G.; Fisicaro, P.; Boni, C. Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C. Cells 2021, 10, 2563. https://doi.org/10.3390/cells10102563
Barili V, Vecchi A, Rossi M, Montali I, Tiezzi C, Penna A, Laccabue D, Missale G, Fisicaro P, Boni C. Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C. Cells. 2021; 10(10):2563. https://doi.org/10.3390/cells10102563
Chicago/Turabian StyleBarili, Valeria, Andrea Vecchi, Marzia Rossi, Ilaria Montali, Camilla Tiezzi, Amalia Penna, Diletta Laccabue, Gabriele Missale, Paola Fisicaro, and Carolina Boni. 2021. "Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C" Cells 10, no. 10: 2563. https://doi.org/10.3390/cells10102563