T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses

Abstract

T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

“…Persistent virus or parasite infection, tumor development, and subsequent repeated antigenic stimulation and chronic inflammation have been associated with functional exhaustion of T cells in both humans and animal models, showing functional impairment of antigen-specific and nonspecific immune cells in activation, proliferation, cytokine production and antibody synthesis. (14,20,21) Specific T cells become exhausted within the chronic inflammatory area of infected organs, thus contributing over the long term to the escape of viruses, parasites, or tumor cells from immune attack. (10,(22)(23)(24) Several key surface molecules, such as PDCD1, LAG3, and CTLA4, which are associated with T-cell exhaustion and the blocking of which may recover the T-cell function, have been recognized and are usually defined as "immunocheckpoints" or more simply "checkpoints."…”

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

“…High expressions are generally believed to be markers of exhausted T cells during the chronic stage. While previous studies and reviews concentrated on “classical” ICs of PD‐1 and CTLA‐4, emerging studies unravel crucial roles of “the next generation” ICs of TIGIT, LAG‐3, BTLA, and other ICs in chronic viral infections, which will be the focus of this section.…”

“…Failure of T‐cell–mediated immunity to overcome viral infections is relevant to chronic hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections, which are responsible for significant mortality and morbidity in the human population . A prolonged and continuous encounter with the cognate viral antigen alters T‐cell differentiation so that the activated virus‐specific T cells progress into a state of nonfunctionality and finally into physical elimination, a phenomenon called “T‐cell exhaustion.” Along with the advances of biomedical techniques, particularly the major histocompatibility complex (MHC) multimer staining to detect virus‐specific CD4 + and CD8 + T cells, biological characterization of exhausted T cells has been extensively explored. Among the most prominent characteristic of exhausted T cells is overexpression of ICs, leading to an excessive negative regulation exerted on T cells …”

T cell metabolism in chronic viral infection

“…In CD4 + T cells the expression of PD-1 is associated with a down-regulation of glycolysis and an up-regulation of FAO and lipolysis [70]. capable of producing more than one cytokine) and are found in long-term non-progressors [71]. capable of producing more than one cytokine) and are found in long-term non-progressors [71].…”

“…In HIV-1, T cells expressing lower levels of PD-1 are more polyfunctional (i.e. capable of producing more than one cytokine) and are found in long-term non-progressors [71]. Interestingly, while genetic deletion of PD-1 in human TCR-redirected transgenic T cells leads to an increased capacity for virus-specific killing, the complete genetic absence of PD-1 is correlated with reduced survival of the T cell pool in the context of chronic infection [72,73].…”