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

Alireza Saeidi, Keivan Zandi, Yi Ying Cheok, Hamidreza Saeidi, Won Fen Wong, Chalystha Yie Qin Lee, Heng Choon Cheong, Yean Kong Yong, Marie Larsson, Esaki Muthu Shankar, Alireza Saeidi, Keivan Zandi, Yi Ying Cheok, Hamidreza Saeidi, Won Fen Wong, Chalystha Yie Qin Lee, Heng Choon Cheong, Yean Kong Yong, Marie Larsson, Esaki Muthu Shankar

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.

Keywords: PD-1; T-bet; T-cell exhaustion; epigenetics; immunotherapy; metabolism; rejuvenation.

Figures

Figure 1
Figure 1
PD-1 signal inhibits T-cell receptor (TCR) signaling pathway through several different mechanisms. (a) PD-1 engagement with PD-L1 or PD-L2 ligands blocks TCR signal transmission by promoting microcluster formation and degradation of TCR. Accumulation of PD-1 within the synapse stabilizes the interaction between T cells and antigen presenting cells causing “immune paralysis” and cell motility arrest. PD-1 ligation also enhances TCR internalization and degradation by Casitas B-lymphoma (CBL)-B E3 ubiquitin ligase. (b) PD-1 signaling recruits SHP2 phosphatase to immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). SHP2 dephosphorylates ZAP70, ERK1/2 and suppresses the phosphatidylinositide 3 kinase (PI3K)/AKT/Mammalian Target of Rapamyc from (mTOR) pathways, thus inhibiting multiple T-cell activation pathways. (c) PD-1 suppresses T-cell proliferation by blocking the transcription of Skp1/Cullin/F-box protein ubiquitin ligase (SKP2), which controls cyclin-dependent kinases (Cdks) activation. A Basic leucine transcription factor, ATF-like (BATF) is also a downstream target of PD-1 signaling that causes repression of T-cell proliferation and cytokine secretion. Besides, by inhibiting TCR signaling, PD-1 blocks IL-2 production to limit T-cell proliferation. (d) PD-1 signaling promotes FOXO1 retention in nucleus and enables Pdcd1 gene transactivation. Nuclear factor of activated T cells (NFATc1) in the absence of AP-1 interaction promotes the expression of Pdcd1 (PD-1 encoding gene). The transcription of Pdcd1 is inhibited by AKT/mTOR signaling, which promotes phosphorylation of FOXO1 and 14-3-3 docking to sequester FOXO1 molecule from the nucleus into the cytoplasm. PD-1 signaling stops the process by targeting the AKT/mTOR pathway.
Figure 2
Figure 2
In acute infection, effector CD8 + T cells induce glycolysis after activation to sustain effector functions. Akt and mTOR promote glycolysis and support effector T cell functions. In chronic infection, exhausted T cells express inhibitory receptors such as PD-1 and CTL4. PD-1 signaling reduces AKT activation and thus suppress mTOR activity, switching T cell metabolism from glycolysis to FAO. These metabolic reprogramming may lead to mitochondrial depolarization, reduction of mitochondrial biogenesis and higher rate of ROS production which is associated with functional impairment in exhausted T cells.

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