Abstract
The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein–Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2 (HSV-1/2), and Varicella–Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.
Highlights
The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells
A consequence of accumulating CD8+/CD28− T cells is that they can lose their function, have reduced expression of effector molecules and reduced cytotoxic T-lymphocyte (CTL) activity [33]. These cells have been found in various chronic viral infections, such as human immunodeficiency virus (HIV), Epstein–Barr virus (EBV), and Hepatitis C virus (HCV), with each viral-specific CD8+/CD28− T cell responding with varying degrees of the differentiated phenotype [34]
Evidence is mounting that high levels of antigen stimulation result in excessive proliferation, driving cells into a state of replicative senescence due to telomere attrition
Summary
A rapid immune response occurs between the infected host and the viral pathogen [1]. A consequence of accumulating CD8+/CD28− T cells is that they can lose their function, have reduced expression of effector molecules (granzyme B and perforin) and reduced cytotoxic T-lymphocyte (CTL) activity [33] These cells have been found in various chronic viral infections, such as HIV, Epstein–Barr virus (EBV), and Hepatitis C virus (HCV), with each viral-specific CD8+/CD28− T cell responding with varying degrees of the differentiated phenotype [34]. HIV-specific CD8+ T cells that had undergone replicative senescence, defined by loss of proliferative capacity and shorter telomeres, were found to be more sensitive to apoptosis [39] These cells were not CD28− or C–C chemokine receptor type 7 (CCR7)-deficient, but did harbor CD57 expression, and may not be terminally differentiated. It is likely that less differentiated states (CD27+) are more prone to apoptosis, while late differentiated cells (CD27−) acquire apoptosis resistance, leading to replicative senescence
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