Biomedical subjects

Hugo A van den Berg

Publications and source records attributed to Hugo A van den Berg.

5 recordsLinked to original sources

PubMed2005

Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface.

The off-rate (k(off)) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of >1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity.

Antigens↗

PubMed2004

Foreignness as a matter of degree: the relative immunogenicity of peptide/MHC ligands.

The ability of T lymphocytes (T cells) to recognize and attack foreign invaders while leaving healthy cells unharmed is often analysed as a discrete self/non-self dichotomy, with each peptide/MHC ligand classified as either self or non-self. We argue that the ligand immunogenicity is more naturally treated as a continuous quantity, and show how to define and quantitate relative ligand immunogenicity. In our theory, self-tolerance is acquired through reduction of the relative immunogenicity of autoantigens, whereas xenoantigens, typically not presented during induction of deletional tolerance, retain a high degree of relative immunogenicity. Autoantigens that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. According to our analysis, any given autoantigen can attain a high level of relative immunogenicity, provided it is presented at sufficiently high levels. Our theory provides a quantitative tool to analyse the immunogenicity of tumour-associated neoantigens and the aetiology of autoimmune disease.

Antigens, Neoplasm↗

PubMed2004

Dynamics of T cell activation threshold tuning.

T lymphocytes are believed to alter their sensitivity to TCR stimulation by means of a tunable cellular activation threshold. We present two modelling examples which show that the concept of a tunable threshold can be made mechanistically plausible. The tunable threshold is treated as an emergent property of the dynamics of the T cell's signalling machinery. In addition, we discuss how the dynamic properties of activation threshold tuning can be determined experimentally with the aid of these two models. We propose a novel 'avidity selection' mechanism for the initial stages of the immune response, based on the properties of the T cell activation threshold tuning mechanism we propose for the commitment to differentiation. Our main finding is that activation threshold tuning allows T cells to respond to relevant ligands with a detection threshold that is (i) uniform across both the T cell repertoire and the secondary lymphoid tissues, while (ii) retaining tolerance to autostimulation. Our analysis indicates that central tolerance enhances the efficiency of peripheral tolerance, casting new light on the role of negative selection in the thymus.

Animals↗

PubMed2003

Antigen presentation on MHC molecules as a diversity filter that enhances immune efficacy.

We consider the way in which antigen is presented to T cells on MHC molecules and ask how MHC peptide presentation could be optimized so as to obtain an effective and safe immune response. By analysing this problem with a mathematical model of T-cell activation, we deduce the need for both MHC restriction and high presentation selectivity. We find that the optimal selectivity is such that about one pathogen-derived peptide is presented per MHC isoform, on the average. We also indicate upper and lower bounds to the number of MHC isoforms per individual based on detectability requirements. Thus we deduce that an important role of MHC presentation is to act as a filter that limits the diversity of antigen presentation.

Animals↗

PubMed2002

Optimal allocation of building blocks between nutrient uptake systems in a microbe.

A bacterial cell must distribute its molecular building blocks among various types of nutrient uptake systems. If the microbe is to maximize its average growth rate, this allocation of building blocks must be adjusted to the environmental availabilities of the various nutrients. The adjustments can be found from growth balancing considerations. We give a full proof of optimality and uniqueness of the optimal allocation regime for a simple model of microbial growth and internal stores kinetics. This proof suggests likely candidates for optimal control regimes in the case of a more realistic model. These candidate regimes differ with respect to the information that the cell's control system must have access to. We pay particular attention to one of the three candidates, a feedback regime based on a cellular control system that monitors only internal reserve densities. We show that allocation converges rapidly to balanced growth under this control regime.

Adaptation, Psychological↗