The TCR assigns naive T cells to a preferred lymph node.

Naive T cells recirculate between the spleen and lymph nodes where they mount immune responses when meeting dendritic cells presenting foreign antigen. As this may happen anywhere, naive T cells ought to visit all lymph nodes. Here, deep sequencing almost-complete TCR repertoires led to a comparison of different lymph nodes within and between individual mice.

Is the exquisite specificity of lymphocytes generated by thymic selection or due to evolution?

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.

Better safe than sorry: Naive T-cell dynamics in healthy ageing.

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.

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.

Challenges in cybersecurity: Lessons from biological defense systems.

Defending against novel, repeated, or unpredictable attacks, while avoiding attacks on the 'self', are the central problems of both mammalian immune systems and computer systems. Both systems have been studied in great detail, but with little exchange of information across the different disciplines. Here, we present a conceptual framework for structured comparisons across the fields of biological immunity and cybersecurity, by framing the context of defense, considering different (combinations of) defensive strategies, and evaluating defensive performance.

What explains the poor contraction of the viral load during paediatric HIV infection?

An acute HIV infection in young children differs markedly from that in adults: Children have higher viral loads (VL), and a poor contraction to a setpoint VL that is not much lower than the peak VL. As a result, children progress faster towards AIDS in the absence of treatment. We used a classical ordinary differential equation model for viral infection dynamics to study why children have a lower viral contraction ratio than adults.

Modeling T Cell Fate.

Many of the pathways that underlie the diversification of naive T cells into effector and memory subsets, and the maintenance of these populations, remain controversial. In recent years a variety of experimental tools have been developed that allow us to follow the fates of cells and their descendants. In this review we describe how mathematical models provide a natural language for describing the growth, loss, and differentiation of cell populations.

Age-Dependent Normalization Functions for T Lymphocytes in Healthy Individuals.

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).

Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis.

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here, we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in juvenile idiopathic arthritis (JIA).

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.

Quantification of CD4 Recovery in Early-Treated Infants Living With HIV.

Background: Perinatally HIV-acquired infants benefit from an early antiretroviral treatment initiation. Thanks to a short viral exposure time, their immune system can be maintained or reconstituted, allowing a "normal" immune development.

Methods: In this study, we mathematically modeled and quantified individual CD4+ T-cell reconstitution of a subset of 276 children who started treatment within 6 months of age and achieved sustained viral suppression.

Replicative history marks transcriptional and functional disparity in the CD8 T cell memory pool.

Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8 memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo.

Turnover of Murine Cytomegalovirus-Expanded CD8 T Cells Is Similar to That of Memory Phenotype T Cells and Independent of the Magnitude of the Response.

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.

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans.

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.

Hematopoiesis in numbers.

Hematopoiesis is a dynamic process in which stem and progenitor cells give rise to the ~10 blood and immune cells distributed throughout the human body. We argue that a quantitative description of hematopoiesis can help consolidate existing data, identify knowledge gaps, and generate new hypotheses. Here, we review known numbers in murine and, where possible, human hematopoiesis, and consolidate murine numbers into a set of reference values.

The limitations, dangers, and benefits of simple methods for testing identifiability.

In their Commentary paper, Villaverde and Massonis (On testing structural identifiability by a simple scaling method: relying on scaling symmetries can be misleading) have commented on our paper in which we proposed a simple scaling method to test structural identifiability. Our scaling invariance method (SIM) tests for scaling symmetries only, and Villaverde and Massonis correctly show the SIM may fail to detect identifiability problems when a model has other types of symmetries. We agree with the limitations raised by these authors but, also, we emphasize that the method is still valuable for its applicability to a wide variety of models, its simplicity, and even as a tool to introduce the problem of identifiability to investigators with little training in mathematics.

TCRβ rearrangements without a D segment are common, abundant, and public.

T cells play an important role in adaptive immunity. An enormous clonal diversity of T cells with a different specificity, encoded by the T cell receptor (TCR), protect the body against infection. Most TCRβ chains are generated from a V, D, and J segment during recombination in the thymus.

Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity.

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, "yes/no" process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of "additive cytotoxicity" by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination.

Local actin dynamics couple speed and persistence in a cellular Potts model of cell migration.

Cell migration is astoundingly diverse. Molecular signatures, cell-cell interactions, and environmental structures each play their part in shaping cell motion, yielding numerous morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently.

Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT.

Lymphocyte numbers need to be quite tightly regulated. It is generally assumed that lymphocyte production and lifespan increase homeostatically when lymphocyte numbers are low and, vice versa, return to normal once cell numbers have normalized. This widely accepted concept is largely based on experiments in mice, but is hardly investigated in vivo in humans.

Testing structural identifiability by a simple scaling method.

Successful mathematical modeling of biological processes relies on the expertise of the modeler to capture the essential mechanisms in the process at hand and on the ability to extract useful information from empirical data. A model is said to be structurally unidentifiable, if different quantitative sets of parameters provide the same observable outcome. This is typical (but not exclusive) of partially observed problems in which only a few variables can be experimentally measured.

CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells .

Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in multiple inflammatory and fibrotic diseases.

Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy.

Background: Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART.

Setting: From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days.

The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes.

The clone size distribution of the human naive T-cell receptor (TCR) repertoire is an important determinant of adaptive immunity. We estimated the abundance of TCR sequences in samples of naive T cells from blood using an accurate quantitative sequencing protocol. We observe most TCR sequences only once, consistent with the enormous diversity of the repertoire.