Joost B. Beltman

MHC polymorphism under host-pathogen coevolution

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under host-pathogen coevolution, despite the fact that allele frequencies continuously change.

Heterogeneous Differentiation Patterns of Individual CD8+ T Cells

Dynamic Protection During an immune response, CD8+ T cells are recruited to provide protection. Most cells differentiate into short-lived effectors that help to clear the pathogen, whereas others form long-lived memory cells to protect against reinfection. Gerlach et al. (p. 635, published online 14 March) and Buchholz et al. (p. 630, published online 14 March) used in vivo fate mapping of mouse T cells with a defined specificity during a bacterial infection to show that the dynamics of the single-cell response are not uniform. The response of a particular T cell population is the average of a small number of clones that expand greatly (“large clones”) and many clones that only proliferate at low amounts (“small clones”). The memory pool arises largely from small clones whereas effectors are primarily made up of large clones. The single-cell dynamics as cytotoxic T cells respond to a bacterial infection are analyzed in mice. Upon infection, antigen-specific CD8+ T lymphocyte responses display a highly reproducible pattern of expansion and contraction that is thought to reflect a uniform behavior of individual cells. We tracked the progeny of individual mouse CD8+ T cells by in vivo lineage tracing and demonstrated that, even for T cells bearing identical T cell receptors, both clonal expansion and differentiation patterns are heterogeneous. As a consequence, individual naïve T lymphocytes contributed differentially to short- and long-term protection, as revealed by participation of their progeny during primary versus recall infections. The discordance in fate of individual naïve T cells argues against asymmetric division as a singular driver of CD8+ T cell heterogeneity and demonstrates that reproducibility of CD8+ T cell responses is achieved through population averaging.

Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen

Recent work has demonstrated that following the clearance of infection a stable population of memory T cells remains present in peripheral organs and contributes to the control of secondary infections. However, little is known about how tissue-resident memory T cells behave in situ and how they encounter newly infected target cells. Here we demonstrate that antigen-specific CD8+ T cells that remain in skin following herpes simplex virus infection show a steady-state crawling behavior in between keratinocytes. Spatially explicit simulations of the migration of these tissue-resident memory T cells indicate that the migratory dendritic behavior of these cells allows the detection of antigen-expressing target cells in physiologically relevant time frames of minutes to hours. Furthermore, we provide direct evidence for the identification of rare antigen-expressing epithelial cells by skin-patrolling memory T cells in vivo. These data demonstrate the existence of skin patrol by memory T cells and reveal the value of this patrol in the rapid detection of renewed infections at a previously infected site.

Analysing immune cell migration

The visualization of the dynamic behaviour of and interactions between immune cells using time-lapse video microscopy has an important role in modern immunology. To draw robust conclusions, quantification of such cell migration is required. However, imaging experiments are associated with various artefacts that can affect the estimated positions of the immune cells under analysis, which form the basis of any subsequent analysis. Here, we describe potential artefacts that could affect the interpretation of data sets on immune cell migration. We propose how these errors can be recognized and corrected, and suggest ways to prevent the data analysis itself leading to biased results.

TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

Speciation: more likely through a genetic or through a learned habitat preference?

A problem in understanding sympatric speciation is establishing how reproductive isolation can arise when there is disruptive selection on an ecological trait. One of the solutions that has been proposed is that a habitat preference evolves, and that mates are chosen within the preferred habitat. We present a model where the habitat preference can evolve either by means of a genetic mechanism or by means of learning. Employing an adaptive-dynamical analysis, we show that evolution proceeds either to a single population of specialists with a genetic preference for their optimal habitat, or to a population of generalists without a habitat preference. The generalist population subsequently experiences disruptive selection. Learning promotes speciation because it increases the intensity of disruptive selection. An individual-based version of the model shows that, when loci are completely unlinked and learning confers little cost, the presence of disruptive selection most probably leads to speciation via the simultaneous evolution of a learned habitat preference. For high costs of learning, speciation is most likely to occur via the evolution of a genetic habitat preference. However, the latter only happens when the effect of mutations is large, or when there is linkage between genes coding for the different traits.

LEARNING AND COLONIZATION OF NEW NICHES: A FIRST STEP TOWARD SPECIATION

Abstract Learning processes potentially play a role in speciation but are often ignored in speciation models. Learning may, for instance, play a role when a new niche is being colonized, because the learning of niche features may cause niche‐specific assortative mating and a tendency to produce young in this niche. Several animal species learn about their environmental features that may be important in finding or attracting mates. We use a gene‐culture coevolutionary model to look into the effect of such learning on the colonization of new niches and on the genetic divergence between groups using different niches, which are steps necessary in achieving speciation. We assume that density is regulated separately in each of the two niches and that the viability of an individual depends on its genotype as well as on which niche it exploits. Our results show that genetic adaptation to the new niche is enhanced by a high female fecundity and a low viability selection against heterozygotes. Furthermore, when initial colonization (without genetic adaptation) fails, genetic divergence is more difficult when the mating preference is stronger. In contrast, when colonization without genetic adaptation is successful, a stronger mating preference makes genetic divergence easier. An increase in the number of egg‐laying mistakes by females can have a positive or negative effect on the success of genetic adaptation depending on other parameters. We show that genetic divergence can be prevented by a niche shift, which can occur only if viabilities in the two niches are asymmetrical.

Spatial modelling of brief and long interactions between T cells and dendritic cells.

In the early phases of an immune response, T cells of appropriate antigen specificity become activated by antigen‐presenting cells in secondary lymphoid organs. Two‐photon microscopy imaging experiments have shown that this stimulation occurs in distinct stages during which T cells exhibit different motilities and interactions with dendritic cells (DCs). In this paper, we utilize the Cellular Potts Model, a model formalism that takes cell shapes and cellular interactions explicitly into account, to simulate the dynamics of, and interactions between, T cells and DCs in the lymph node paracortex. Our three‐dimensional simulations suggest that the initial decrease in T‐cell motility after antigen appearance is due to ‘stop signals’ transmitted by activated DCs to T cells. The long‐lived interactions that occur at a later stage can only be explained by the presence of both stop signals and a high adhesion between specific T cells and antigen‐bearing DCs. Furthermore, our results indicate that long‐lasting contacts with T cells are promoted when DCs retract dendrites that detect a specific contact at lower velocities than other dendrites. Finally, by performing long simulations (after prior fitting to short time scale data) we are able to provide an estimate of the average contact duration between T cells and DCs.

Combination Approaches with immune-Checkpoint Blockade in Cancer Therapy

In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

B cells within germinal centers migrate preferentially from dark to light zone

One of the main questions in the field of imaging immune cell migration in living tissues is whether cells fulfill their functionality via random or nonrandom migration processes. For some applications, this issue has remained controversial even after publication of various imaging studies. A prime example is B-cell migration in germinal centers (GCs) where somatic hypermutation and clonal selection of B cells are thought to occur within morphologically distinct regions termed dark zone (DZ) and light zone (LZ). Here, we reanalyze a previously published dataset on GC B-cell migration, applying a sensitive analysis technique to detect directed migration and using a procedure to correct for a number of artifacts that frequently occur in time-lapse imaging experiments. Although B cells roughly perform a persistent random walk, we present evidence that they have a small preference (of on average about 0.2−0.3 μm min−1) to migrate from DZ to LZ, which is consistent with classical views of the GC reaction. This preference is most pronounced among a large subset of almost half of the B-cell population migrating along relatively straight tracks. Using a computational model to generate long-lasting B-cell tracks based on the experimental motility data (including the small directional preference), we predict a time course to travel from DZ to LZ of a few hours. This is consistent with experimental observations, and we show that at the observed cellular motility such a time course cannot be explained without the small preferential migration from DZ to LZ.