Is there a link between economic outcomes and genetic evolution? Cross-country evidence from the major histocompatibility complex

This research develops a theory and presents empirical evidence of a link between economicoutcomes and genetic evolution. Important properties for successful analysis of such a link arefound in the adaptive immune system and particularly in the major histocompatibilitycomplex (MHC), a genetically encoded complex involved in the defence against infections.The theory incorporates properties of the MHC in a model of mutual dependence and exhibitsa trade-off in which every agent who is better off having an immune response different fromthat of others is also part of the protecting belt of others in a population, in which mountingsimilar immune responses is optimal. The data are based on large numbers of blood samplesfrom 63 different populations. The cross-country estimates show a robust negative associationbetween economic and health outcomes and MHC diversity and between average offers inultimatum and trust games and MHC diversity. The analyses suggest that societiesincorporating externalities from mutual dependence are economically more successful, andthat the incorporation of such externalities is evident at the gene level.education, training and the labour market;

Explicit kinetic heterogeneity: mechanistic models for interpretation of labeling data of heterogeneous cell populations

Estimation of division and death rates of lymphocytes in different conditions is vital for quantitative understanding of the immune system. Deuterium, in the form of deuterated glucose or heavy water, can be used to measure rates of proliferation and death of lymphocytes in vivo. Inferring these rates from labeling and delabeling curves has been subject to considerable debate with different groups suggesting different mathematical models for that purpose. We show that the three models that are most commonly used are in fact mathematically identical and differ only in their interpretation of the estimated parameters. By extending these previous models, we here propose a more mechanistic approach for the analysis of data from deuterium labeling experiments. We construct a model of "kinetic heterogeneity" in which the total cell population consists of many sub-populations with different rates of cell turnover. In this model, for a given distribution of the rates of turnover, the predicted fraction of labeled DNA accumulated and lost can be calculated. Our model reproduces several previously made experimental observations, such as a negative correlation between the length of the labeling period and the rate at which labeled DNA is lost after label cessation. We demonstrate the reliability of the new explicit kinetic heterogeneity model by applying it to artificially generated datasets, and illustrate its usefulness by fitting experimental data. In contrast to previous models, the explicit kinetic heterogeneity model 1) provides a mechanistic way of interpreting labeling data; 2) allows for a non-exponential loss of labeled cells during delabeling, and 3) can be used to describe data with variable labeling length

Effect of cellular aging on memory T-cell homeostasis

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

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

On the feasibility of using TCR sequencing to follow a vaccination response – lessons learned

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

Abundance of Early Functional HIV-Specific CD8+ T Cells Does Not Predict AIDS-Free Survival Time

Background T-cell immunity is thought to play an important role in controlling HIV infection, and is a main target for HIV vaccine development. HIV-specific central memory CD8+ and CD4+ T cells producing IFNγ and IL-2 have been associated with control of viremia and are therefore hypothesized to be truly protective and determine subsequent clinical outcome. However, the cause-effect relationship between HIV-specific cellular immunity and disease progression is unknown. We investigated in a large prospective cohort study involving 96 individuals of the Amsterdam Cohort Studies with a known date of seroconversion whether the presence of cytokine-producing HIV-specific CD8+ T cells early in infection was associated with AIDS-free survival time. Methods and Findings The number and percentage of IFNγ and IL-2 producing CD8+ T cells was measured after in vitro stimulation with an overlapping Gag-peptide pool in T cells sampled approximately one year after seroconversion. Kaplan-Meier survival analysis and Cox proportional hazard models showed that frequencies of cytokine-producing Gag-specific CD8+ T cells (IFNγ, IL-2 or both) shortly after seroconversion were neither associated with time to AIDS nor with the rate of CD4+ T-cell decline. Conclusions These data show that high numbers of functional HIV-specific CD8+ T cells can be found early in HIV infection, irrespective of subsequent clinical outcome. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression

Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments.

Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in different studies. Notably, deuterated (2)H2-glucose (D2-glucose) labeling studies consistently yield higher estimates of proliferation than deuterated water (D2O) labeling studies. This hampers our understanding of immune function and undermines our confidence in this important technique. Whether these differences are caused by fundamental biochemical differences between the two compounds and/or by methodological differences in the studies is unknown. D2-glucose and D2O labeling experiments have never been performed by the same group under the same experimental conditions; consequently a direct comparison of these two techniques has not been possible. We sought to address this problem. We performed both in vitro and murine in vivo labeling experiments using identical protocols with both D2-glucose and D2O. This showed that intrinsic differences between the two compounds do not cause differences in the proliferation rate estimates, but that estimates made using D2-glucose in vivo were susceptible to difficulties in normalization due to highly variable blood glucose enrichment. Analysis of three published human studies made using D2-glucose and D2O confirmed this problem, particularly in the case of short term D2-glucose labeling. Correcting for these inaccuracies in normalization decreased proliferation rate estimates made using D2-glucose and slightly increased estimates made using D2O; thus bringing the estimates from the two methods significantly closer and highlighting the importance of reliable normalization when using this technique

HLA Alleles Associated with Slow Progression to AIDS Truly Prefer to Present HIV-1 p24

Background: The mechanism behind the association between human leukocyte antigen (HLA) molecules and the rate of HIV-1 disease progression is still poorly understood. Recent data suggest that ‘‘protective’’ HLA molecules, i.e. those associated with a low HIV-1 viral load and relatively slow disease progression, tend to present epitopes from the Gag capsid protein. Although this suggests that preferential targeting of Gag delays disease progression, the apparent preference for Gag could also be a side-effect of the relatively high immunogenicity of the protein. Methods and Findings: To separate cause and effect, we predicted HIV-1 epitopes from the whole genome of HIV-1, and found that protective HLA alleles have a true preference for the p24 Gag protein, while non-protective HLA alleles preferentially target HIV-1 Nef. In line with this, we found a significant negative correlation between the predicted affinity of the best-binding p24 epitopes and the relative hazard of HIV-1 disease progression for a large number of HLA molecules. When the epitopes targeted by protective HLA alleles were mapped to the known p24 structure, we found that mutations in these epitopes are likely to disturb the p24 dimer structure, which is expected to severely reduce the fitness of the virus. Conclusions: Our results suggest that the intrinsic preference of different HLA molecules to present p24 peptides explains why some HLA molecules are more protective than others