Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27‐year‐long longitudinal study

Samson, Leonard Daniël; Berg, Sara P. H. van den; Engelfriet, Peter; Boots, Annemieke M. H.; Hendriks, Marion; Rond, Lia G. H. de; Zeeuw-Brouwer, Mary lène de; Borghans, José A. M.; Buisman, Anne Marie; Baarle, Debbie van

doi:10.1002/cti2.1193

Cited by 24 publications

(52 citation statements)

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“…Although we cannot rule out the possibility that small differences in production/loss rates may have been missed in our in vivo deuterium labelling study, our data suggest that high CD8 + CMV-specific T-cell numbers do not go hand in hand with substantial differences in the average production or loss rates of these cells. The large size of the CMV-specific T-cell pool is possibly set shortly after CMV infection [ 41 ], though the underlying mechanisms explaining these large CMV-specific expansions remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans

et al. 2021

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Cytomegalovirus (CMV) infection has a major impact on the T-cell pool, which is thought to be associated with ageing of the immune system. The effect on the T-cell pool has been interpreted as an effect of CMV on non-CMV specific T-cells. However, it remains unclear whether the effect of CMV could simply be explained by the presence of large, immunodominant, CMV-specific memory CD8+ T-cell populations. These have been suggested to establish through gradual accumulation of long-lived cells. However, little is known about their maintenance. We investigated the effect of CMV infection on T-cell dynamics in healthy older adults, and aimed to unravel the mechanisms of maintenance of large numbers of CMV-specific CD8+ T-cells. We studied the expression of senescence, proliferation, and apoptosis markers and quantified the in vivo dynamics of CMV-specific and other memory T-cell populations using in vivo deuterium labelling. Increased expression of late-stage differentiation markers by CD8+ T-cells of CMV+ versus CMV- individuals was not solely explained by the presence of large, immunodominant CMV-specific CD8+ T-cell populations. The lifespans of circulating CMV-specific CD8+ T-cells did not differ significantly from those of bulk memory CD8+ T-cells, and the lifespans of bulk memory CD8+ T-cells did not differ significantly between CMV- and CMV+ individuals. Memory CD4+ T-cells of CMV+ individuals showed increased expression of late-stage differentiation markers and decreased Ki-67 expression. Overall, the expression of senescence markers on T-cell populations correlated positively with their expected in vivo lifespan. Together, this work suggests that i) large, immunodominant CMV-specific CD8+ T-cell populations do not explain the phenotypical differences between CMV+ and CMV- individuals, ii) CMV infection hardly affects the dynamics of the T-cell pool, and iii) large numbers of CMV-specific CD8+ T-cells are not due to longer lifespans of these cells.

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Section: Discussionmentioning

confidence: 99%

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans

et al. 2021

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“…We cannot exclude the possibility that the older individuals of the study population had been infected at an older age, possibly leading to an antigen-specific T-cell repertoire of lower diversity because the diversity of the naive (precursor) pool is known to decrease with age (Britanova et al, 2014 ; Egorov et al, 2018 ). However, the recent finding that only a very small percentage of individuals seroconvert for CMV at later age (Samson et al, 2020 ), as well as the finding that more than 90% of the population is infected with EBV during adolescence (Balfour et al, 2013 ; Winter et al, 2020 ), makes this explanation unlikely. In our view, a more likely explanation for the reduced diversity in the antigen-specific T-cell repertoire of older individuals would be that older individuals have been infected for a longer time, and have lost more T-cell clones over time, for example due to exhaustion after restimulation (Lanfermeijer et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

et al. 2021

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CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.

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“…D+ or R+ patients had significantly lower functional status in comparison to their contemporaneous D-R- counterparts. Although the mechanism underlying these associations is not fully understood, growing body of evidence in immunocompetent hosts suggests that latent state CMV (indicative of CMV seropositivity) may have unique role in the development of and/or acceleration of age-related frailty and functional impairment [ 5 , 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…The virus even in its transcriptionally quiescent state continues to express immediate-early genes without progression to the productive forms of the virus [ 21 , 22 , 23 ]. The ensuing immunostimulatory and inflammatory state triggered by chronic antigenic stimulation over time leads to host cell damage and manifestations of frailty and functional decline [ 6 , 7 ]. CMV antibody levels, considered to reflect multiple CMV reactivations experienced during life, correlated with cognitive decline in older individuals, even when controlled for other risk factors such as age and chronic health conditions [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…CMV seropositivity is indicative of latent state of the virus during which subclinical and low-level replication occurs throughout the lifetime of an individual [ 6 ]. The persistent antigen exposure and resultant low-grade inflammatory state has the potential to accelerate host cell and tissue damage leading to frailty, progression of aging and ultimately death [ 6 , 7 ]. Comprehensive assessment of immune profiling in a large cohort of healthy aging adults showed that CMV serostatus was among the factors with most impact on immune dysfunction with aging [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus Serostatus and Functional Impairment in Liver Transplant Recipients in the Current Era

Singh

Wagener

2021

Viruses

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Background: Whether donor (D+) or recipient (R+) cytomegalovirus (CMV) seropositivity is associated with functional impairment in liver transplant recipients is not known. Methods: Patients included adult liver transplant recipients in the Organ Procurement and Transplantation Network database transplanted over a five-year period from 1 January 2014–31 December 2018. Functional status in the database was assessed using Karnofsky performance scale. A logistic regression model that controlled for potential confounders was used to examine the association of CMV serostatus and functional status. Variables significantly associated with functional status (p < 0.05) were then used to develop propensity score and propensity score matched analysis was conducted where each patient was compared with a matched-control with the same propensity score. Results: Among 30,267 adult liver transplant recipients, D+ or R+ patients had significantly lower functional status at last follow-up than the D-R- cohort (OR 0.88, 95% CI 0.80–0.96, p = 0.007). In propensity score matched model, D+ or R+ patients had significantly lower functional status than matched-controls (p = 0.009). D+ or R+ CMV serostatus (p = 0.018) and low functional level (p < 0.001) were also independently associated with infections as cause-of-death. Conclusions: D+ or R+ liver transplant recipients had lower functional status and higher risk of deaths due to infections. Future studies are warranted to examine the mechanistic basis of these findings in the setting of transplantation.

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Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27‐year‐long longitudinal study

Cited by 24 publications

References 72 publications

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans

Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire

Cytomegalovirus Serostatus and Functional Impairment in Liver Transplant Recipients in the Current Era

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