Abstract
Emerging studies show that T cell exhaustion correlates well with increased expression levels of inhibitory receptors including Programmed cell death receptor 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) during chronic infections. Both inhibitory molecules play similar but non-redundant role in T cell exhaustion. Engagement of PD-1 and CTLA-4 by their ligands inhibits T cell proliferation, cytokine secretion, and attenuates immune responses. Blockade of PD-1 and CTLA-4 restores effector function of exhausted T cells. PD-1 and CTLA-4 could both recruit Src homology 2-containing tyrosine phosphatase 2 (SHP2) and inhibit activation of Akt. Nevertheless, PD-1 and CTLA-4 also target distinct signaling molecules to inhibit T cell function. In this review, we will discuss current understanding of PD-1 and CTLA-4 initiated signaling pathways, their regulatory roles in a variety of chronic viral infections, and their promising potential as targets to enhance T cell function for antiviral therapy.
Highlights
Chronic viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), are great threats to human health, and developing effective therapies against those infections is a big challenge
Recent studies have revealed that inhibitory receptors, programmed cell death receptor 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), are involved in the process of T cell exhaustion during chronic viral infections
CTLA-4 is 30% homologous to CD28 and shares the same ligands CD80/86 with CD28 in antigen presenting cells (APCs) [8,9]
Summary
Chronic viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), are great threats to human health, and developing effective therapies against those infections is a big challenge. PD-1 plays a key role in cytotoxic T lymphocyte (CTL) exhaustion during chronic viral infections, indicating that PD-1 negatively regulates CD8+ T cell effector function. Contrast to inhibitory signals delivered by CTLA-4, engagement of CD28 favors T cell activation, proliferation and effective cytokines secretion.
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