Andrew Yates

Memory CD8 T-cell compartment grows in size with immunological experience

Memory CD8 T cells, generated by natural pathogen exposure or intentional vaccination, protect the host against specific viral infections. It has long been proposed that the number of memory CD8 T cells in the host is inflexible, and that individual cells are constantly competing for limited space. Consequently, vaccines that introduce over-abundant quantities of memory CD8 T cells specific for an agent of interest could have catastrophic consequences for the host by displacing memory CD8 T cells specific for all previous infections. To test this paradigm, we developed a vaccination regimen in mice that introduced as many new long-lived memory CD8 T cells specific for a single vaccine antigen as there were memory CD8 T cells in the host before vaccination. Here we show that, in contrast to expectations, the size of the memory CD8 T-cell compartment doubled to accommodate these new cells, a change due solely to the addition of effector memory CD8 T cells. This increase did not affect the number of CD4 T cells, B cells or naive CD8 T cells, and pre-existing memory CD8 T cells specific for a previously encountered infection were largely preserved. Thus, the number of effector memory CD8 T cells in the mammalian host adapts according to immunological experience. Developing vaccines that abundantly introduce new memory CD8 T cells should not necessarily ablate pre-existing immunity to other infections.

Virulence-transmission trade-offs and population divergence in virulence in a naturally occurring butterfly parasite

Why do parasites harm their hosts? Conventional wisdom holds that because parasites depend on their hosts for survival and transmission, they should evolve to become benign, yet many parasites cause harm. Theory predicts that parasites could evolve virulence (i.e., parasite-induced reductions in host fitness) by balancing the transmission benefits of parasite replication with the costs of host death. This idea has led researchers to predict how human interventions—such as vaccines—may alter virulence evolution, yet empirical support is critically lacking. We studied a protozoan parasite of monarch butterflies and found that higher levels of within-host replication resulted in both higher virulence and greater transmission, thus lending support to the idea that selection for parasite transmission can favor parasite genotypes that cause substantial harm. Parasite fitness was maximized at an intermediate level of parasite replication, beyond which the cost of increased host mortality outweighed the benefit of increased transmission. A separate experiment confirmed genetic relationships between parasite replication and virulence, and showed that parasite genotypes from two monarch populations caused different virulence. These results show that selection on parasite transmission can explain why parasites harm their hosts, and suggest that constraints imposed by host ecology can lead to population divergence in parasite virulence.

The ecology of nasal colonization of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus: the role of competition and interactions with host's immune response

BackgroundThe first step in invasive disease caused by the normally commensal bacteria Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae is their colonization of the nasal passages. For any population to colonize a new habitat it is necessary for it to be able to compete with the existing organisms and evade predation. In the case of colonization of these species the competition is between strains of the same and different species of bacteria and the predation is mediated by the hosts immune response. Here, we use a neonatal rat model to explore these elements of the ecology of nasal colonization by these occasionally invasive bacteria.ResultsWhen neonatal rats are colonized by any one of these species the density of bacteria in the nasal passage rapidly reaches a steady-state density that is species-specific but independent of inoculum size. When novel populations of H. influenzae and S. pneumoniae are introduced into the nasal passages of neonatal rats with established populations of the same species, residents and invaders coexisted. However, this was not the case for S. aureus - the established population inhibited invasion of new S. aureus populations. In mixed-species introductions, S. aureus or S. pneumoniae facilitated the invasion of another H. influenzae population; for other pairs the interaction was antagonistic and immune-mediated. For example, under some conditions H. influenzae promoted an immune response which limited the invasion of S. pneumoniae.ConclusionsNasal colonization is a dynamic process with turnover of new strains and new species. These results suggest that multiple strains of either H. influenzae or S. pneumoniae can coexist; in contrast, S. aureus strains require a host to have no other S. aureus present to colonize. Levels of colonization (and hence the possible risk of invasive disease) by H. influenzae are increased in hosts pre-colonized with either S. aureus or S. pneumoniae.

Quantifying the development of the peripheral naive CD4+ T-cell pool in humans

What are the rules that govern a naive T cells prospects for survival or division after export from the thymus into the periphery? To help address these questions, we combine data from existing studies with robust mathematical models to estimate the absolute contributions of thymopoiesis, peripheral division, and loss or differentiation to the human naive CD4+ T-cell pool between the ages of 0 and 20 years. Despite their decline in frequency in the blood, total body numbers of naive CD4+ T cells increase throughout childhood and early adulthood. Our analysis shows that postthymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved with age; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens. We also show that the expected residence time of naive T cells increases with time. The naive CD4+ T-cell population thus becomes progressively less dynamic with age. Together with other studies, our results suggest a complex picture of naive T-cell homeostasis in which population size, time since export from the thymus, or time since the last division can influence a cells prospects for survival or further divisions.

Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4+ and CD8+ T cells

Naïve T cells continually recirculate between blood and secondary lymphoid organs, scanning dendritic cells (DC) for foreign antigen. Despite its importance for understanding how adaptive immune responses are efficiently initiated from rare precursors, a detailed quantitative analysis of this fundamental process has not been reported. Here we measure lymph node (LN) entry, transit, and exit rates for naïve CD4+ and CD8+ T cells, then use intravital imaging and mathematical modeling to relate cell–cell interaction dynamics to population behavior. Our studies reveal marked differences between CD4+ vs. CD8+ T cells. CD4+ T cells recirculate more rapidly, homing to LNs more efficiently, traversing LNs twice as quickly, and spending ∼1/3 of their transit time interacting with MHCII on DC. In contrast, adoptively transferred CD8+ T cells enter and leave the LN more slowly, with a transit time unaffected by the absence of MHCI molecules on host cells. Together, these data reveal an unexpectedly asymmetric role for MHC interactions in controlling CD4+ vs. CD8+ T lymphocyte recirculation, as well as distinct contributions of T cell receptor (TCR)-independent factors to the LN transit time, exposing the divergent surveillance strategies used by the two lymphocyte populations in scanning for foreign antigen.

Quantifying Thymic Export: Combining Models of Naive T Cell Proliferation and TCR Excision Circle Dynamics Gives an Explicit Measure of Thymic Output

Understanding T cell homeostasis requires knowledge of the export rate of new T cells from the thymus, a rate that has been surprisingly difficult to estimate. TCR excision circle (TREC) content has been used as a proxy for thymic export, but this quantity is influenced by cell division and loss of naive T cells and is not a direct measure of thymic export. We present in this study a method for quantifying thymic export in humans by combining two simple mathematical models. One uses Ki67 data to calculate the rate of peripheral naive T cell production, whereas the other tracks the dynamics of TRECs. Combining these models allows the contributions of the thymus and cell division to the daily production rate of T cells to be disentangled. The method is illustrated with published data on Ki67 expression and TRECs within naive CD4+ T cells in healthy individuals. We obtain a quantitative estimate for thymic export as a function of age from birth to 20 years. The export rate of T cells from the thymus follows three distinct phases, as follows: an increase from birth to a peak at 1 year, followed by rapid involution until ∼8 years, and then a more gradual decline until 20 years. The rate of involution shown by our model is compatible with independent estimates of thymic function predicted by thymic epithelial space. Our method allows nonintrusive estimation of thymic output on an individual basis and may provide a means of assessing the role of the thymus in diseases such as HIV.

The dynamics of acute malaria infections. I. Effect of the parasite's red blood cell preference

What determines the dynamics of parasite and anaemia during acute primary malaria infections? Why do some strains of malaria reach higher densities and cause greater anaemia than others? The conventional view is that the fastest replicating parasites reach the highest densities and cause the greatest loss of red blood cells (RBCs). Other current hypotheses suggest that the maximum parasite density is achieved by strains that either elicit the weakest immune responses or infect the youngest RBCs (reticulocytes). Yet another hypothesis is a simple resource limitation model where the peak parasite density and the maximum anaemia (percentage loss of RBCs) during the acute phase of infection equal the fraction of RBCs that the malaria parasite can infect. We discriminate between these hypotheses by developing a mathematical model of acute malaria infections and confronting it with experimental data from the rodent malaria parasite Plasmodium chabaudi. We show that the resource limitation model can explain the initial dynamics of infection of mice with different strains of this parasite. We further test the model by showing that without modification it closely reproduces the dynamics of competing strains in mixed infections of mice with these strains of P. chabaudi. Our results suggest that a simple resource limitation is capable of capturing the basic features of the dynamics of both parasite and RBC loss during acute malaria infections of mice with P. chabaudi, suggesting that it might be worth exploring if similar results might hold for other acute malaria infections, including those of humans.

How do pathogen evolution and host heterogeneity interact in disease emergence

Heterogeneity in the parameters governing the spread of infectious diseases is a common feature of real-world epidemics. It has been suggested that for pathogens with basic reproductive number R0>1, increasing heterogeneity makes extinction of disease more likely during the early rounds of transmission. The basic reproductive number R0 of the introduced pathogen may, however, be less than 1 after the introduction, and evolutionary changes are then required for R0 to increase to above 1 and the pathogen to emerge. In this paper, we consider how host heterogeneity influences the emergence of both non-evolving pathogens and those that must undergo adaptive changes to spread in the host population. In contrast to previous results, we find that heterogeneity does not always make extinction more likely and that if adaptation is required for emergence, the effect of host heterogeneity is relatively small. We discuss the application of these ideas to vaccination strategies.

Fratricide: a mechanism for T memory-cell homeostasis

Immunological memory depends on a self-renewing pool of antigen-specific T memory (Tm) cells but the homeostatic mechanisms that maintain the size and diversity of the pool are largely unknown. Competition for space or growth factors has been suggested as a mechanism but how these factors themselves are regulated is unclear. We suggest that Tm-cell fratricide by Fas-mediated apoptosis results in a density-dependent death rate that controls the size of the pool without requiring competition for resources or an external quorum-sensing mechanism. A mathematical model based on this concept predicts the known behaviour of the Tm pool, including observed differences in heterogeneity of the CD4 and CD8 compartments and might provide a paradigm for homeostasis of other haematopoietic-cell populations.

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

Significance Thymocytes express a diverse repertoire of T-cell antigen receptors. Stringent selection processes eliminate autoreactive cells and guide useful thymocytes to develop into CD4 or CD8 lineages. Development always generates more CD4 than CD8 T cells, but it is not understood why. Our study used mathematics to investigate the basis of this asymmetric lineage development. Although similar numbers of CD4 and CD8 precursors start selection, our analysis revealed unexpectedly high death rates in developing thymocytes. In particular, CD8 precursors were more susceptible to death than CD4 lineage cells, and this was a major contributor to the high CD4:CD8 ratio of development. It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis.