Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C

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.

Metabolic plasticity and regulation of T cell exhaustion

“…T cell metabolism and differentiation are regulated by various cytokines including IL‐2, IL‐7, IL‐10, IL‐12 and IL‐21 (Figure 2). Among them, IL‐2, IL‐7 and IL‐21 are the members of γ‐chain cytokine family and play an important role in antagonizing exhaustion 77 . Both IL‐2 and IL‐7 are critical for T cell differentiation and homeostasis by regulating metabolism.…”

“…Among them, IL-2, IL-7 and IL-21 are the members of γ-chain cytokine family and play an important role in antagonizing exhaustion. 77 Both IL-2 and IL-7 are critical for T cell differentiation and homeostasis by regulating metabolism. IL-2 treatment could promote glycolysis by activating the mTOR pathway, thereby altering cell differentiation and effector functions.…”

Interleukin-21 in Viral Infections

“…HCV causes chronic infection in 65-85% of affected people, and there are approximately 180 million chronic HCV patients worldwide [123]. Similar to HBV, IL-21's function against HCV infection is thought to be mainly based on the recovery of exhausted CD8+ T cells [124]. It is clear that CD8 + T cells and CD4 + T cells play an important role in acute HCV infection [125,126].…”

T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

“…Indeed, at least the synergic effect of anti-PDL1 and IL7 has been tested in vitro, showing to be effective on HCV-specific CD8 cell reactivity. Analogously, IL15 or IL21 combined with PD1 blockade display the potential for exhausted CD8 T cell restoration [ 6 ].…”