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

Objectives: Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation.Methods: We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint.Results: In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4+ T-cell numbers and frailty.Conclusion: Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.</p

Current best estimates for the average lifespans of mouse and human leukocytes : reviewing two decades of deuterium-labeling experiments

Deuterium is a non-toxic, stable isotope that can safely be administered to humans and mice to study their cellular turnover rates in vivo. It is incorporated into newly synthesized DNA strands during cell division, without interference with the kinetics of cells, and the accumulation and loss of deuterium in the DNA of sorted (sub-)populations of leukocytes can be used to estimate their cellular production rates and lifespans. In the past two decades, this powerful technology has been used to estimate the turnover rates of various types of leukocytes. Although it is the most reliable technique currently available to study leukocyte turnover, there are remarkable differences between the cellular turnover rates estimated by some of these studies. We have recently established that part of this variation is due to (a) difficulties in estimating deuterium availability in some deuterium-labeling studies, and (b) assumptions made by the mathematical models employed to fit the data. Being aware of these two problems, we here aim to approach a consensus on the life expectancies of different types of T cells, B cells, monocytes, and neutrophils in mice and men. We address remaining outstanding problems whenever appropriate and discuss for which immune subpopulations we currently have too little information to draw firm conclusions about their turnover

Maternal vaccination against RSV can substantially reduce childhood mortality in low-income and middle-income countries: A mathematical modeling study

Background: Respiratory syncytial virus (RSV) is a leading cause of childhood mortality in infants below 6 months of age. In low-income and middle-income countries (LMICs), the public health burden is substantial and resources are limited. It is critical to inform decision makers about effectiveness of new interventions. Methods: We developed a mathematical model where individual RSV subtype A (RSV-A) and B (RSV-B) maternally derived neutralizing titers were predicted at time of birth after maternal vaccination with the RSV prefusion F protein-based vaccine. We estimated the subsequent duration of vaccine-induced immunity and compared this to the age at time of death distribution in the RSV GOLD Mortality Database to predict the potential impact of maternal vaccination on RSV-related childhood mortality. We used country-specific timing of antenatal care visits distributions and mortality estimates to make country-specific predictions for number of cases averted. Findings: The model predicts that on average a neonate born at 40 weeks gestational age will be protected between 6 and 7 months from RSV-A and approximately 5 months from RSV-B related mortality. We estimated the potential impact of RSV-related mortality for in-hospital and out-of-hospital cases in LMICs and predicted that in 51 GAVI-eligible countries maternal vaccination could avert between 55% and 63% of the RSV-related in-hospital mortality cases below 6 months of age. Interpretation: We show that maternal vaccination could substantially decrease RSV-A and RSV-B related in-hospital and out-of-hospital mortality in LMICs in the first 6 months of life

Dynamics of recent thymic emigrants in young adult mice

The peripheral naive T-cell pool is generally thought to consist of a subpopulation of recent thymic emigrants (RTEs) and a subpopulation of mature naive (MN) T cells with different dynamics. Thymus transplantation and adoptive transfer studies in mice have provided contradicting results, with some studies suggesting that RTEs are relatively short-lived cells, while another study suggested that RTEs have a survival advantage. We here estimate the death rates of RTE and MN T cells by performing both thymus transplantations and deuterium labeling experiments in mice of at least 12 weeks old, an age at which the size of the T-cell pool has stabilized. For CD4 ++ T cells, we found the total loss rate from the RTE compartment (by death and maturation) to be fourfold faster than that of MN T cells. We estimate the death rate of CD4+ RTE to be 0.046 per day, which is threefold faster than the total loss rate from the MN T-cell compartment. For CD8+ T cells, we found no evidence for kinetic differences between RTE and MN T cells. Thus, our data support the notion that in young adult mice, CD4+ RTE are relatively short-lived cells within the naive CD4++ T-cell pool

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals

Age-related distribution and dynamics of T-cells in blood and lymphoid tissues of goats

Neonatal mammals have increased disease susceptibility and sub-optimal vaccine responses. This raises problems in both humans and farm animals. The high prevalence of paratuberculosis in goats and the lack of an effective vaccine against it have a strong impact on the dairy sector, and calls for vaccines optimized for the neonatal immune system. We characterized the composition of the T-cell pool in neonatal kids and adult goats and quantified their turnover rates using in vivo deuterium labelling. From birth to adulthood, CD4+ T-cells were the predominant subset in the thymus and lymph nodes, while spleen and bone marrow contained mainly CD8+ lymphocytes. In blood, CD4+ T-cells were the predominant subset during the neonatal period, while CD8+ T-cells predominated in adults. We observed that thymic mass and cellularity increased during the first 5 months after birth, but decreased later in life. Deuterium labelling revealed that T-cell turnover rates in neonatal kids are considerably higher than in adult animals.</p