Search

The human leukocyte antigen (HLA) B57 allele and the closely related HLA-B5801 allele are overrepresented among human immunodeficiency virus type 1 (HIV-1)-infected individuals with a long-term nonprogressive clinical course of disease (known as 'long-term nonprogressors' [LTNPs]). These alleles are, however, also present among individuals with normal disease progression (known as 'progressors'). In a comparison of HLA-B57/5801-expressing progressors and LTNPs, we observed a similar prevalence of escape mutations in 4 Nef epitopes and a similar reactivity of CD8+ T cells against 3 of 4 of these epitopes and their autologous escape variants. However, LTNPs tended to have frequent and preserved CD8+ T cell interferon-gamma responses against the wild-type HW9 Nef epitope, whereas progressors did not maintain a specific CD8+ T cell response. This finding is in line with the findings of a more exhausted phenotype of CD8+ T cells in progressors, as is demonstrated by their enhanced level of expression of inhibitory receptor 'programmed death 1' (PD-1). The results of the present study suggest that preservation of HW9-specific T cell responses is associated with a more benign clinical course of infection. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

To protect older adults against influenza A virus (IAV) infection, innovative strategies are imperative to overcome the decrease in protective immune response with age. One approach involves the boosting of CD8+ T cells at middle age that were previously induced by natural infection. At this stage, the immune system is still fit. Given the high conservation of T-cell epitopes within internal viral proteins, such a response may confer lasting protection against evolving influenza strains at older age, also reducing the high number of influenza immunizations currently required. However, at the time of vaccination, some individuals may have been more recently exposed to IAV than others, which could affect the T-cell response. We therefore investigated the fundamental principle of how the interval between the last infection and booster immunization during middle age influences the CD8+ T-cell response. To model this, female mice were infected at either 6 or 9 months of age and subsequently received a heterosubtypic infection booster at middle age (12 months). Before the booster infection, 6-month-primed mice displayed lower IAV-specific CD8+ T-cell responses in the spleen and lung than 9-month-primed mice. Both groups were better protected against the subsequent heterosubtypic booster infection compared to naïve mice. Notably, despite the different CD8+ T-cell levels between the 6-month- and 9-month-primed mice, we observed comparable responses after booster infection, based on IFNγ responses, and IAV-specific T-cell frequencies and repertoire diversity. Lung-derived CD8+ T cells of 6- and 9-month-primed mice expressed similar levels of tissue-resident memory-T-cell markers 30 days post booster infection. These data suggest that the IAV-specific CD8+ T-cell response after boosting is not influenced by the time post priming., Competing Interests: J.L. is currently working at AstraZeneca in the Netherlands. However, when performing this research and while writing the first versions of the manuscript, this was not the case. S.L. is currently working at MSD, the Netherlands; however, when performing this research, this was not the case. All the other authors declare no competing interests.

We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal 'specificity' level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of self-antigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also become more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two -not mutually exclusive- explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional post-selection repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the pre-selection repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 De Boer, Kesmir, Perelson and Borghans.)

The European Medicines Agency and the US Food and Drug Administration have recently approved a maternal vaccine for respiratory syncytial virus. The US Food and Drug Administration limits vaccination to later in pregnancy. Mathematical modeling demonstrates that this vaccination window may reduce the global mortality impact of the vaccine by 12%. Policymakers should carefully consider vaccine risks and benefits to safeguard vulnerable infants effectively., Competing Interests: L.J.B. has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100,000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received major funding as part of the public-private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1,000–25,000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Janssen. L.J.B. is the founding chairman of the ReSViNET Foundation. Since April 1, 2021, Louis has been given a new position as medical scientific division manager of the Children’s Division of the Wilhelmina Children’s Hospital in Utrecht. The other authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

It is well-known that the functioning of the immune system gradually deteriorates with age, and we are increasingly confronted with its consequences as the life expectancy of the human population increases. Changes in the T-cell pool are among the most prominent features of the changing immune system during healthy ageing, and changes in the naive T-cell pool in particular are generally held responsible for its gradual deterioration. These changes in the naive T-cell pool are thought to be due to involution of the thymus. It is commonly believed that the gradual loss of thymic output induces compensatory mechanisms to maintain the number of naive T cells at a relatively constant level, and induces a loss of diversity in the T-cell repertoire. Here we review the studies that support or challenge this widely-held view of immune ageing and discuss the implications for vaccination strategies., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100,000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1,000–25,000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, Janssen. Dr. Bont is the founding chairman of the ReSViNET Foundation. Since April 1st 2021, LB has been given a new position as medical scientific division manager of the Children's Division of the Wilhelmina Children's Hospital in Utrecht., (© 2023 The Author(s).)

Background: Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis., Objective: To define and compare biomarkers of disease severity and progression in psoriatic skin., Methods: We performed proteome profiling to study the proteins circulating in the serum from patients with psoriasis, psoriatic arthritis and ankylosing spondylitis, and transcriptome sequencing to investigate the gene expression in skin from the same cohort. We then used machine learning approaches to evaluate different biomarker candidates across several independent cohorts. In order to reveal the cell-type specificity of different biomarkers, we also analyzed a single-cell dataset of skin samples. In-situ staining was applied for the validation of biomarker expression., Results: We identified that the peptidase inhibitor 3 (PI3) was significantly correlated with the corresponding local skin gene expression, and was associated with disease severity. We applied machine learning methods to confirm that PI3 was an effective psoriasis classifier, Finally, we validated PI3 as psoriasis biomarker using in-situ staining and public datasets. Single-cell data and in-situ staining indicated that PI3 was specifically highly expressed in keratinocytes from psoriatic lesions., Conclusion: Our results suggest that PI3 may be a psoriasis-specific biomarker for disease severity and hyper-keratinization., Competing Interests: Declaration of Competing Interest TR, AP and WT is currently an employee of AbbVie, with no conflicts of interest regarding the work of this manuscript. The other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

CD8 + T cells are promising targets for vaccination against influenza A virus (IAV) infection. Their induction via peptide vaccination is not trivial, because peptides are weakly immunogenic. One strategy to overcome this is by vaccination with chemically enhanced altered peptide ligands (CPLs), which have improved MHC-binding and immunogenicity. It remains unknown how peptide-modification affects the resulting immune response. We studied the effect of CPLs derived from the influenza M1 58-66 epitope (GILGFVFTL) on the T-cell response. In HLA-A2*0201 transgenic mice, CPL-vaccination led to higher T-cell frequencies, but only a small percentage of the induced T cells recognized the GILG-wildtype (WT) peptide. CPL-vaccination resulted in a lower richness of the GILG-WT-specific T-cell repertoire and no improved protection against IAV-infection compared to GILG-WT peptide-vaccination. One CPL even appeared to enhance pathology after IAV-challenge. CPL-vaccination thus induces T cells not targeting the original peptide, which may lead to potential unwanted side effects., (© 2023. Springer Nature Limited.)

T cells recognize pathogens by their highly specific T-cell receptor (TCR), which can bind small fragments of an antigen presented on the Major Histocompatibility Complex (MHC). Antigens that are provided through vaccination cause specific T cells to respond by expanding and forming specific memory to combat a future infection. Quantification of this T-cell response could improve vaccine monitoring or identify individuals with a reduced ability to respond to a vaccination. In this proof-of-concept study we use longitudinal sequencing of the TCRβ repertoire to quantify the response in the CD4+ memory T-cell pool upon pneumococcal conjugate vaccination. This comes with several challenges owing to the enormous size and diversity of the T-cell pool, the limited frequency of vaccine-specific TCRs in the total repertoire, and the variation in sample size and quality. We defined quantitative requirements to classify T-cell expansions and identified critical parameters that aid in reliable analysis of the data. In the context of pneumococcal conjugate vaccination, we were able to detect robust T-cell expansions in a minority of the donors, which suggests that the T-cell response against the conjugate in the pneumococcal vaccine is small and/or very broad. These results indicate that there is still a long way to go before TCR sequencing can be reliably used as a personal biomarker for vaccine-induced protection. Nevertheless, this study highlights the importance of having multiple samples containing sufficient T-cell numbers, which will support future studies that characterize T-cell responses using longitudinal TCR sequencing., Competing Interests: JL currently works at AstraZeneca Netherlands. The research described in this study was performed prior to this employment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Greef, Lanfermeijer, Hendriks, Cevirgel, Vos, Borghans, van Baarle and de Boer.)

Memory T cells form an essential part of immunological memory, which can last for years or even a lifetime. Much experimental work has shown that the individual cells that make up the memory T-cell pool are in fact relatively short-lived. Memory T cells isolated from the blood of humans, or the lymph nodes and spleen of mice, live about 5-10 fold shorter than naive T cells, and much shorter than the immunological memory they convey. The commonly accepted view is, therefore, that long-term T-cell memory is maintained dynamically rather than by long-lived cells. This view is largely based on memory T cells in the circulation, identified using rather broad phenotypic markers, and on research in mice living in overly clean conditions. We wondered to what extent there may be heterogeneity in the dynamics and lifespans of memory T cells. We here review what is currently known about the dynamics of memory T cells in different memory subsets, locations in the body and conditions of microbial exposure, and discuss how this may be related to immunometabolism and how this knowledge can be used in various clinical settings., (© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Lymphocyte numbers naturally change through age. Normalization functions to account for this are sparse and mostly disregard measurements from children in which these changes are most prominent. In this study, we analyze cross-sectional numbers of mainly T lymphocytes (CD3+, CD3+CD4+, and CD3+CD8+) and their subpopulations (naive and memory) from 673 healthy Dutch individuals ranging from infancy to adulthood (0-62 y). We fitted the data by a delayed exponential function and estimated parameters for each lymphocyte subset. Our modeling approach follows general laboratory measurement procedures in which absolute cell counts of T lymphocyte subsets are calculated from observed percentages within a reference population that is truly counted (typically the total lymphocyte count). Consequently, we obtain one set of parameter estimates per T cell subset representing both the trajectories of their counts and percentages. We allow for an initial time delay of half a year before the total lymphocyte counts per microliter of blood start to change exponentially, and we find that T lymphocyte trajectories tend to increase during the first half a year of life. Thus, our study provides functions describing the general trajectories of T lymphocyte counts and percentages of the Dutch population. These functions provide important references to study T lymphocyte dynamics in disease, and they allow one to quantify losses and gains in longitudinal data, such as the CD4+ T cell decline in HIV-infected children and/or the rate of T cell recovery after the onset of treatment., (Copyright © 2023 by The American Association of Immunologists, Inc.)

A timely recovery of T-cell numbers following haematopoietic stem-cell transplantation (HSCT) is essential for preventing complications, such as increased risk of infection and disease relapse. In analogy to the occurrence of lymphopenia-induced proliferation in mice, T-cell dynamics in humans are thought to be homeostatically regulated in a cell density-dependent manner. The idea is that T cells divide faster and/or live longer when T-cell numbers are low, thereby helping the reconstitution of the T-cell pool. T-cell reconstitution after HSCT is, however, known to occur notoriously slowly. In fact, the evidence for the existence of homeostatic mechanisms in humans is quite ambiguous, since lymphopenia is often associated with infectious complications and immune activation, which confound the study of homeostatic regulation. This calls into question whether homeostatic mechanisms aid the reconstitution of the T-cell pool during lymphopenia in humans. Here we review the changes in T-cell dynamics in different situations of T-cell deficiency in humans, including the early development of the immune system after birth, healthy ageing, HIV infection, thymectomy and hematopoietic stem cell transplantation (HSCT). We discuss to what extent these changes in T-cell dynamics are a side-effect of increased immune activation during lymphopenia, and to what extent they truly reflect homeostatic mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baliu-Piqué, Tesselaar and Borghans.)

The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this 'homeostatic' regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, 'global' competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional 'cognate' competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the 'gold-standard'. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for 'cognate' competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the 'gold-standard' level of TCR diversity in the memory T-cell pool., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Swain, Borghans and de Boer.)

Psoriasis is a chronic inflammatory skin disorder. Although it has been studied extensively, the molecular mechanisms driving the disease remain unclear. In this study, we utilized a tree-based machine learning approach to explore the gene regulatory networks underlying psoriasis. We then validated the regulators and their networks in an independent cohort. We identified some key regulators of psoriasis, which are candidates to serve as potential drug targets and disease severity biomarkers. According to the gene regulatory network that we identified, we suggest that interferon signaling represents a key pathway of psoriatic inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deng, Schieler, Borghans, Lu and Pandit.)

The potential of memory T cells to provide protection against reinfection is beyond question. Yet, it remains debated whether long-term T cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8 + T cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T cells, depending on factors such as exposure to cognate Ag. CMV infection induces not only conventional, contracting T cell responses, but also inflationary CD8 + T cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8 + T cells. Using in vivo deuterium labeling and mathematical modeling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8 + T cells are very similar to those of bulk memory-phenotype CD8 + T cells. Even CMV-specific inflationary CD8 + T cell responses that differ 3-fold in size were found to turn over at similar rates., (Copyright © 2022 by The American Association of Immunologists, Inc.)

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., Competing Interests: The authors have declared that no competing interests exist.

Waning of the mumps virus (MuV)-specific humoral response after vaccination has been suggested as a cause for recent mumps outbreaks in vaccinated young adults, although it cannot explain all cases. Moreover, CD8 + T cells may play an important role in the response against MuV; however, little is known about the characteristics and dynamics of the MuV-specific CD8 + T-cell response after MuV infection. Here, we had the opportunity to follow the CD8 + T-cell response to three recently identified HLA-A2*02:01-restricted MuV-specific epitopes from 1.5 to 36 months post-MuV infection in five previously vaccinated and three unvaccinated individuals. The infection-induced CD8 + T-cell response was dominated by T cells specific for the ALDQTDIRV and LLDSSTTRV epitopes, while the response to the GLMEGQIVSV epitope was subdominant. MuV-specific CD8 + T-cell frequencies in the blood declined between 1.5 and 9 months after infection. This decline was not explained by changes in the expression of inhibitory receptors or homing markers. Despite the ongoing changes in the frequencies and phenotype of MuV-specific CD8 + T cells, TCRβ analyses revealed a stable MuV-specific T-cell repertoire over time. These insights in the maintenance of the cellular response against mumps may provide hallmarks for optimizing vaccination strategies towards a long-term cellular memory response.

Latent infection with cytomegalovirus (CMV) is assumed to contribute to the age-associated decline of the immune system. CMV induces large changes in the T-cell pool and may thereby affect other immune responses. CMV is expected to impact especially older adults, who are already at higher risk of severe disease and hospitalization upon infections such as influenza virus (IAV) infection. Here, we investigated the impact of CMV infection on IAV-specific CD8 + T-cell frequencies in healthy individuals (n=96) and the response to IAV infection in older adults (n=72). IAV-specific memory T-cell frequencies were lower in healthy CMV + older individuals compared to healthy CMV - older individuals. Upon acute IAV infection, CMV serostatus or CMV-specific antibody levels were not negatively associated with IAV-specific T-cell frequencies, function, phenotype or T-cell receptor repertoire diversity. This suggests that specific T-cell responses upon acute IAV infection are not negatively affected by CMV. In addition, we found neither an association between CMV infection and inflammatory cytokine levels in serum during acute IAV infection nor between cytokine levels and the height of the IAV-specific T-cell response upon infection. Finally, CMV infection was not associated with increased severity of influenza-related symptoms. In fact, CMV infection was even associated with increased IAV-specific T-cell responses early upon acute IAV infection. In conclusion, although associated with lower frequencies of memory IAV-specific T cells in healthy individuals, CMV infection does not seem to hamper the induction of a proper T-cell response during acute IAV infection in older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van den Berg, Lanfermeijer, Jacobi, Hendriks, Vos, van Schuijlenburg, Nanlohy, Borghans, van Beek, van Baarle and de Wit.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lanfermeijer, de Greef, Hendriks, Vos, van Beek, Borghans and van Baarle.)

The human genome encodes more than 300 potential immune inhibitory receptors. The reason for this large number of receptors remains unclear. We suggest that inhibitory receptors operate as two distinct functional categories: receptors that control the signalling threshold for immune cell activation and receptors involved in the negative feedback of immune cell activation. These two categories have characteristic receptor expression patterns: 'threshold' receptors are expressed at steady state and their expression remains high or is downregulated upon activation, whereas 'negative feedback' receptors are induced upon immune cell activation. We use mathematical models to illustrate their possible modes of operation in different scenarios for different purposes. We discuss how this categorization may impact the choice of therapeutic targets for immunotherapy of malignant, infectious and autoimmune diseases.

Older adults often show signs of impaired CD8 + T-cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T-cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long-term maintenance of the antigen-specific T-cell repertoire. Here, we review the literature on the maintenance of antigen-experienced CD8 + T-cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T-cell repertoire, and the effects of age, infection history, and T-cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD8 + T-cells, %CD70 + CD4 + T-cells, %CD169 + monocytes, and absolute CD4 + T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003-1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR + CD4 + T-cells, %HLA-DR + CD38 + CD4 + T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065-1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

Latent infection with cytomegalovirus (CMV) is thought to accelerate aging of the immune system. With age, influenza vaccine responses are impaired. Although several studies investigated the effect of CMV infection on antibody responses to influenza vaccination, this led to contradicting conclusions. Therefore, we investigated the relation between CMV infection and the antibody response to influenza vaccination by performing a systematic review and meta-analysis. All studies on the antibody response to influenza vaccination in association with CMV infection were included (n = 17). The following outcome variables were extracted: (a) the geometric mean titer pre-/post-vaccination ratio (GMR) per CMV serostatus group, and in addition (b) the percentage of subjects with a response per CMV serostatus group and (c) the association between influenza- and CMV-specific antibody titers. The influenza-specific GMR revealed no clear evidence for an effect of CMV seropositivity on the influenza vaccine response in young or old individuals. Meta-analysis of the response rate to influenza vaccination showed a non-significant trend towards a negative effect of CMV seropositivity. However, funnel plot analysis suggests that this is a consequence of publication bias. A weak negative association between CMV antibody titers and influenza antibody titers was reported in several studies, but associations could not be analyzed systematically due to the variety of outcome variables. In conclusion, by systematically integrating the available studies, we show that there is no unequivocal evidence that latent CMV infection affects the influenza antibody response to vaccination. Further studies, including the level of CMV antibodies, are required to settle on the potential influence of latent CMV infection on the influenza vaccine response.

The maintenance and dynamics of memory T-cells in the bone marrow are a matter of ongoing debate. It has been suggested that memory T-cells in the bone marrow are maintained as long-lived, quiescent cells. We have recently shown that memory T-cells isolated from goat bone marrow undergo self-renewal and recirculate via the blood and lymph. Using the well-established memory T-cell markers CD44 and CD62L we here show very similar results in mice. This provides further support for the concept that memory T-cells are continuously self-renewing and recirculating between blood, bone marrow, spleen and lymph nodes., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2018. Published by Elsevier Ltd.)

Memory T-cells are essential to maintain long-term immunological memory. It is widely thought that the bone marrow (BM) plays an important role in the long-term maintenance of memory T-cells. There is controversy however on the longevity and recirculating kinetics of BM memory T-cells. While some have proposed that the BM is a reservoir for long-lived, non-circulating memory T-cells, it has also been suggested to be the preferential site for memory T-cell self-renewal. In this study, we used in vivo deuterium labeling in goats to simultaneously quantify the average turnover rates-and thereby expected lifespans-of memory T-cells from BM, blood and lymph nodes (LN). While the fraction of Ki-67 positive cells, a snapshot marker for recent cell division, was higher in memory T-cells from blood compared to BM and LN, in vivo deuterium labeling revealed no substantial differences in the expected lifespans of memory T-cells between these compartments. Our results support the view that the majority of memory T-cells in the BM are self-renewing as fast as those in the periphery, and are continuously recirculating between the blood, BM, and LN.

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Respiratory syncytial virus (RSV) infection is an important cause of infant mortality. Here, we estimated the potential impact of maternal vaccination against RSV on life-threatening RSV infection in infants., Methods: We developed a mathematical model for maternal vaccine-induced antibody dynamics and used characteristics of a maternal RSV vaccine currently in phase 3 of clinical development. The model was applied to data from two cohorts of children younger than 12 months with RSV-related paediatric intensive care unit (PICU) admission in the United Kingdom (n = 370) and the Netherlands (n = 167), and a cohort of 211 children younger than 12 months with RSV-related in-hospital death from 20 countries worldwide., Results: Our model predicted that, depending on vaccine efficiency, maternal vaccination at 30 weeks' gestational age could have prevented 62-75% of RSV-related PICU admissions in the United Kingdom and 76-87% in the Netherlands. For the global mortality cohort, the model predicted that maternal vaccination could have prevented 29-48% of RSV-related in-hospital deaths. Preterm children and children with comorbidities were predicted to benefit less than (healthy) term children., Conclusions: Maternal vaccination against RSV may substantially decrease life-threatening RSV infections in infants., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

Both healthy aging and human immunodeficiency virus (HIV) infection lead to a progressive decline in naive CD8 + T-cell numbers and expansion of the CD8 + T-cell memory and effector compartments. HIV infection is therefore often considered a condition of premature aging. Total CD8 + T-cell numbers of HIV-infected individuals typically stay increased even after long-term (LT) combination antiretroviral treatment (cART), which is associated with an increased risk of non-AIDS morbidity and mortality. The causes of these persistent changes in the CD8 + T-cell pool remain debated. Here, we studied the impact of age, CMV infection, and LT successful cART on absolute cell numbers in different CD8 + T-cell subsets. While naïve CD8 + T-cell numbers in cART-treated individuals ( N  = 38) increased to healthy levels, central memory (CM), effector memory (EM), and effector CD8 + T-cell numbers remained higher than in (unselected) age-matched healthy controls ( N  = 107). Longitudinal analysis in a subset of patients showed that cART did result in a loss of memory CD8 + T-cells, mainly during the first year of cART, after which memory cell numbers remained relatively stable. As CMV infection is known to increase CD8 + T-cell numbers in healthy individuals, we studied whether any of the persistent changes in the CD8 + T-cell pools of cART-treated patients could be a direct reflection of the high CMV prevalence among HIV-infected individuals. We found that EM and effector CD8 + T-cell numbers in CMV + healthy individuals ( N  = 87) were significantly higher than in CMV - ( N  = 170) healthy individuals. As a result, EM and effector CD8 + T-cell numbers in successfully cART-treated HIV-infected individuals did not deviate significantly from those of age-matched CMV + healthy controls ( N  = 39). By contrast, CM T-cell numbers were quite similar in CMV + and CMV - healthy individuals across all ages. The LT expansion of the CM CD8 + T-cell pool in cART-treated individuals could thus not be attributed directly to CMV and was also not related to residual HIV RNA or to the presence of HIV-specific CM T-cells. It remains to be investigated why the CM CD8 + T-cell subset shows seemingly irreversible changes despite years of effective treatment.

An association between T-cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T-cell lymphopenia affects B-cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T-cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1-5 years post-Tx, n = 10-27) and older children (>10 years, n = 26), and compared to healthy age-matched controls. T-cell and B-cell subsets were assessed and autoantibody profiling performed. Early post-Tx, a decrease in T-cell numbers (2.75 × 10 9 /L vs. 0.71 × 10 9 /L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B-cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx., (© 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

During acute inflammation, 3 neutrophil subsets are found in the blood: neutrophils with a conventional segmented nucleus, neutrophils with a banded nucleus, and T-cell-suppressing CD62L dim neutrophils with a high number of nuclear lobes. In this study, we compared the in vivo kinetics and proteomes of banded, mature, and hypersegmented neutrophils to determine whether these cell types represent truly different neutrophil subsets or reflect changes induced by lipopolysaccharide (LPS) activation. Using in vivo pulse-chase labeling of neutrophil DNA with 6,6- 2 H 2 -glucose, we found that 2 H-labeled banded neutrophils appeared much earlier in blood than labeled CD62L dim and segmented neutrophils, which shared similar label kinetics. Comparison of the proteomes by cluster analysis revealed that CD62L dim neutrophils were clearly separate from conventional segmented neutrophils despite having similar kinetics in peripheral blood. Interestingly, the conventional segmented cells were more related at a proteome level to banded cells despite a 2-day difference in maturation time. The differences between CD62L dim and mature neutrophils are unlikely to have been a direct result of LPS-induced activation, because of the extremely low transcriptional capacity of CD62L dim neutrophils and the fact that neutrophils do not directly respond to the low dose of LPS used in the study (2 ng/kg body weight). Therefore, we propose CD62L dim neutrophils are a truly separate neutrophil subset that is recruited to the bloodstream in response to acute inflammation. This trial was registered at www.clinicaltrials.gov as #NCT01766414., (© 2017 by The American Society of Hematology.)