Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B

Abstract

Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

“…Therefore, the observed mitochondrial dysfunction in NK cells from obese children may contribute to the observed decreased NK cell numbers and impaired effector function. Indeed, several studies in T lymphocytes, in the context of chronic viral infection, support the argument that mitochondrial dysfunction is linked to lymphocyte dysregulation (29)(30)(31). Fisicaro and colleagues demonstrated that chronic hepatitis B infection resulted in exhausted dysfunctional CD8 T cells, which expressed PD-1 and displayed mitochondrial defects, including elevated mitochondrial ROS, drawing striking similarities to the effect of obesity on NK cells (30).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Recently, by a microarray analysis in chronic viral-infected patients fit has been found that exhausted CD8+ T cells show significant downregulation in the expression of several genes associated with mitochondrial OXPHOS metabolism, and upregulation of the oxidative stress pathway. Moreover, Opa-1 levels were found downregulated in that condition, this being probably linked to an altered respiration capacity, and MitoQ antioxidant treatment reduced ROS levels, increased mitochondrial membrane potential and restored cytokine production in T EX cells [211]. This suggests the existence of an interplay between mitochondrial dynamics, metabolism and ROS accumulation during T cell exhaustion that still needs to be investigated and might be crucial in cancer therapy.…”

Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer

“…27 Exhausted T cells showed defective mitochondrial function and restoration of this function by mitochondria-targeted antioxidants improved T cell function. 28 The concept of T cell dysfunction and exhaustion was first described in the setting of chronic viral infection by the groups of RM Zinkernagel 29 and R Ahmed. 30 31 The first molecular description of exhaustion in human cancer was reported by Rosenberg and H Zarour in melanoma patients 27 32 and by Ochsenbein AF in patients with chronic myeloid leukaemia.…”