Biomedical subjects

V Detours

Publications and source records attributed to V Detours.

6 recordsLinked to original sources

PubMed2000

The paradox of alloreactivity and self MHC restriction: quantitative analysis and statistics.

Although 1-24% of T cells are alloreactive, i.e., respond to MHC molecules encoded by a foreign haplotype, it is generally believed that T cells cannot recognize foreign peptides binding foreign MHC molecules. We show using a quantitative model that, if T cell selection and activation are affinity-driven, then an alloreactivity of 1-24% is incompatible with the textbook notion that self MHC restriction is absolute. If an average of 1% of clones are alloreactive, then according to our model, at most 20-fold more clones should, on average, be activated by antigens presented on self MHC than by antigens presented on foreign MHC. This ratio is at best 5 if alloreactivity is 5%. These results describe average properties of the murine immune system, but not the outcome of individual experiments. Using supercomputer technology, we simulated 100,000 MHC restriction experiments. Although the average restriction ratio was 7.1, restriction was absolute in 10% of the simulated experiments, greater than 100, although not absolute, in 29%, and below 6 in 24%. This extreme variability agrees with experimental estimates. Our analysis suggests that alloreactivity and average self MHC restriction both cannot be high, but that a low average restriction level is compatible with high levels in a significant number of experiments.

Animals↗

PubMed2000

Deriving quantitative constraints on T cell selection from data on the mature T cell repertoire.

The T cell repertoire is shaped in the thymus through positive and negative selection. Thus, data about the mature repertoire may be used to infer information on how TCR generation and selection operate. Assuming that T cell selection is affinity driven, we derive the quantitative constraints that the parameters driving these processes must fulfill to account for the experimentally observed levels of alloreactivity, self MHC restriction and the frequency of cells recognizing a given foreign Ag. We find that affinity-driven selection is compatible with experimental estimates of these latter quantities only if 1) TCRs see more peptide residues than MHC polymorphic residues, 2) the majority of positively selected clones are deleted by negative selection, 3) between 1 and 3.6 clonal divisions occur on average in the thymus after completion of TCR rearrangement, and 4) selection is driven by 103-105 self peptides.

Animals↗

PubMed1999

A quantitative theory of affinity-driven T cell repertoire selection.

Binding of the T cell antigen receptor (TCR) to peptides presented on molecules encoded by major histocompatibility complex (MHC) genes is the key event driving T cell development and activation. Selection of the T cell repertoire in the thymus involves two steps. First, positive selection promotes the survival of cells binding thymic self-MHC-peptide complexes with sufficient affinity. The resulting repertoire is self-MHC restricted: it recognizes foreign peptides presented on self, but not foreign MHC. Second, negative selection deletes cells which may be potentially harmful because their receptors interact with self-MHC-peptide complexes with too high an affinity. The mature repertoire is also highly alloreactive: a large fraction of T cells respond to tissues harboring foreign MHC. We derive mathematical expressions giving the frequency of alloreactivity, the level of self-MHC restriction, and the fraction of the repertoire activated by a foreign peptide, as a function of the parameters driving the generation and selection of the repertoire: self-MHC and self-peptide diversity, the stringencies of positive and negative selection, and the number of peptide and MHC polymorphic residues that contribute to T cell receptor binding. Although the model is based on a simplified digit string representation of receptors, all the parameters but one relate directly to experimentally determined quantities. The only parameter without a biological counterpart has no effect on the model's behavior besides a trivial and easily preventable discretization effect. We further analyse the role of the MHC and peptide contribution to TCR binding, and find that their relative, rather than absolute value, is important in shaping the mature repertoire. This result makes it possible to adopt different physical interpretations for the digit string formalism. We also find that the alloreactivity level can be inferred directly from data on the stringency of selection, and that, in agreement with recent experiments, it is not affected by thymic selection.

HLA Antigens↗

PubMed1999

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection.

Interactions between alphabeta T cell receptors and peptides bound to molecules encoded by the MHC genes underly T cell activation. More than 1% of T cells are activated by foreign (allogenic) MHC molecules, a phenomenon called alloreactivity. Reconciling the high frequency of alloreactivity with the fact that only 1 T cell in 10(4)-10(6) responds to a given foreign antigen presented on self MHC has been a long-standing puzzle. We show, by using a quantitative model, that this difference follows from the affinity model of T cell selection. Further, we demonstrate that highly alloreactive pre- and post-selection repertoires can be obtained without assuming germline bias of T cell receptors toward recognition of allele-specific MHC residues. It has been proposed that alloreactivity occurs because self and foreign MHCs bind different subsets of self peptides or alter their conformation differently. We find that such effects decrease rather than increase alloreactivity. Overall, our results show that the affinity model of T cell selection can quantitatively explain both self MHC restriction and high alloreactivity.

Animals↗

PubMed1996

Size and connectivity of the idiotypic network are independent of the discreteness of the affinity distribution.

Idiotypic interactions may be a factor in the selection of the B cell repertoire. Simulations of an evolving idiotypic network where new clones are introduced on a daily basis have shown that macroscopic properties, such as network size and connectivity, attain stationary values despite the rapid turnover of individual clones, indicating that idiotypic networks possess self-organizing properties. Affinities between antibodies were either zero, low (0.1), or high (1.0) in these simulations. It has been suggested that network properties may change when affinities take arbitrary real values. Here we show that the previous results of De Boer & Perelson on network size and connectivity are not changed when affinities take many different, closely spaced values.

Animals↗

PubMed1994

Development of an idiotypic network in shape space.

Based upon the shape-space formalism, a model of an idiotypic network including both bound and free immunoglobulins is simulated. Our point of interest is the network development in the context of self antigens. The investigations are organized around simulations initiated by various spatial configurations of antigens; the behavior of the system with respect to antigens is analyzed in terms of morphogenetic processes occurring in the shape space. For certain values of the parameters, the network expands by traveling waves. The resulting spatial pattern is a partition of the shape space into zones where introduction of an antigen entails an infinite growth of the clones binding to it, and into zones where, on the contrary, the anti-antigen idiotypes decrease. Among the parameter combinations tested, some produce a partition that remains static whereas others produce a partition that changes in time. For other values of the parameters, the patterns generated do not partition shape space into zones; in these cases, it is observed that the system systematically explodes when an antigen is present.

Animals↗