Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C
Open Access
- 3 March 2021
- Vol. 10 (3), 538
- https://doi.org/10.3390/cells10030538
Abstract
Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.Funding Information
- Instituto de Salud Carlos III (PI19/00206)
- Gilead Sciences (GLD14/00217, GLD16/00014)
This publication has 122 references indexed in Scilit:
- A Randomized, Double-Blind, Placebo-Controlled Assessment of BMS-936558, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1), in Patients with Chronic Hepatitis C Virus InfectionPLOS ONE, 2013
- Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory DevelopmentImmunity, 2012
- A human memory T cell subset with stem cell–like propertiesNature Medicine, 2011
- Autocrine IL-2 is required for secondary population expansion of CD8+ memory T cellsNature Immunology, 2011
- Spontaneous Control of HCV Is Associated With Expression of HLA-B*57 and Preservation of Targeted EpitopesGastroenterology, 2011
- Interleukin-2 and Inflammation Induce Distinct Transcriptional Programs that Promote the Differentiation of Effector Cytolytic T CellsImmunity, 2010
- CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responsesProceedings of the National Academy of Sciences of the United States of America, 2009
- Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription FactorsImmunity, 2009
- Enhancing CD8 T-cell memory by modulating fatty acid metabolismNature, 2009
- Functional Restoration of HCV-Specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and CompartmentalizationGastroenterology, 2008