Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: A systematic review

Weltevrede, Marlies; Eilers, Renske; Melker, Hester E. de; Baarle, Debbie van

doi:10.1016/j.exger.2016.02.005

Cited by 108 publications

(104 citation statements)

References 63 publications

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“…Studies have implicated CMV to be associated with an increased risk of all-cause mortality (37) and to cause detrimental changes to the immune response (27)(28)(29) in older people. The paradox with the association of CMV seropositivity with the loss of immune function in older people is that overt CMV disease as a result of reactivation or new infections is not observed; however, there is an increase in detectable virus in urine in older people (44).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Jackson

Sedikides

Mason

et al. 2017

J Virol

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Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8 ϩ T cell response to HCMV has been extensively studied, the HCMVspecific CD4 ϩ T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-␥) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4 ϩ T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-␥ response was still dominant. CD4 ϩ T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1␤ secretion) effector responses. Importantly, when we measured the CD4 ϩ T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4 ϩ T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4 ϩ T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4 ϩ T cell responses, even those from elderly individuals, are highly functional and are directly antiviral.IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the host's lifetime. The dysfunction of immune cells associated with the long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when people are older. In this study, we investigated the response of a subset of immune cells (CD4 ϩ T cells) to HCMV proteins in healthy donors of all ages, and we demonstrate that the functionality of CD4 ϩ T cells is maintained. We also show that CD4 ϩ T cells produce effector functions in response to HCMV-infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Jackson

Sedikides

Mason

et al. 2017

J Virol

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“…One hallmark of latent HCMV infection is the progressive and substantial expansion of HCMV-specific memory CD8 + T cells over time, with HCMV-specific memory CD4 + T cells accumulating to a lesser extent (Klenerman and Oxenius, 2016; Weltevrede et al, 2016). This accumulation of HCMV-specific memory T cells during viral persistence is termed “memory inflation,” first defined in the mouse CMV (MCMV) infection model (Karrer et al, 2003).…”

Section: Human CMV Infection Memory Inflation and Immunosenescencementioning

confidence: 99%

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

2016

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The ability of the human immune system to protect against infectious disease declines with age and efficacy of vaccination reduces significantly in the elderly. Aging of the immune system, also termed as immunosenescence, involves many changes in human T cell immunity that is characterized by a loss in naïve T cell population and an increase in highly differentiated CD28- memory T cell subset. There is extensive data showing that latent persistent human cytomegalovirus (HCMV) infection is also associated with age-related immune dysfunction in the T cells, which might enhance immunosenescence. Understanding the molecular mechanisms underlying age-related and HCMV-related immunosenescence is critical for the development of effective age-targeted vaccines and immunotherapies. In this review, we will address the role of both aging and HCMV infection that contribute to the T cell senescence and discuss the potential molecular mechanisms in aged T cells.

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“…CMV and HIV infection strongly affect CD8 + T-cell differentiation and maturation, enhancing immunosenescence due to the accumulation of highly differentiated T EM and T TE cells (32, 33). The CD57 antigen has been traditionally used to characterize terminally differentiated “senescent” cells, as CD57 + T-cells exhibit a reduced proliferative capacity and altered functional properties (34).…”

Section: Nk-like Cd8+ T-cells In Virus Infection and Immunosenescencementioning

confidence: 99%

Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens

2016

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Human natural killer (NK)-like CD8+ T-cells are singular T-cells that express both T and NK cell markers such as CD56; their frequencies depend on their differentiation and activation during their lifetime. There is evidence of the presence of these innate CD8+ T-cells in the human umbilical cord, highlighting the necessity of investigating whether the NK-like CD8+ T-cells arise in the early stages of life (gestation). Based on the presence of cell surface markers, these cells have also been referred to as CD8+KIR+ T-cells, innate CD8+ T-cells, CD8+CD28−KIR+ T-cells or NKT-like CD8+CD56+ cells. However, the functional and co-signaling significance of these NK cell receptors on NK-like CD8+ T-cells is less clear. Also, the diverse array of costimulatory and co-inhibitory receptors are spatially and temporally regulated and may have distinct overlapping functions on NK-like CD8+ T-cell priming, activation, differentiation, and memory responses associated with different cell phenotypes. Currently, there is no consensus regarding the functional properties and phenotypic characterization of human NK-like CD8+ T-cells. Environmental factors, such as aging, autoimmunity, inflammation, viral antigen re-exposure, or the presence of persistent tumor antigens have been shown to allow differentiation (“adaptation”) of the NK-like CD8+ T-cells; the elucidation of this differentiation process and a greater understanding of the characteristics of these cells could be important for their eventual in potential therapeutic applications aimed at improving protective immunity. This review will attempt to elucidate an understanding of the characteristics of these cells with the goal toward their eventual use in potential therapeutic applications aimed at improving protective immunity.

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Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: A systematic review

Cited by 108 publications

References 63 publications

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens

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Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: A systematic review

Cited by 108 publications

References 63 publications

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 + T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens

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Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Human Cytomegalovirus (HCMV)-Specific CD4 ⁺ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro