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Positive and negative selection, self-nonself discrimination and the roles of costimulation and anergy.

ABSTRACT: It is still unclear whether the adaptive immune system can perform accurate self-nonself discrimination and what could influence its performance. Starting from simple cellular interaction rules we show that it is possible to achieve perfect self-nonself discrimination in a consistent framework provided positive and negative selection operate during repertoire education, and costimulation and anergy are also considered during T cell activation. In this theory T cell receptors diversity is required for cells to sense differently different peptides; positive selection is needed to guarantee maximal lymphocyte's interactivity and to allow negative selection to reduce conjugation lifetimes maximally; costimulation is necessary to signal that an antigen presenting cell established an uncommon rate of long lived conjugations when presenting foreign peptides; anergy is required to guarantee that these stable contacts involved different T cells and not always the same. These results suggest that accurate self-nonself discrimination can have shaped the adaptive immune system.

SUBMITTER: Mostardinha P

PROVIDER: S-EPMC3480656 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Positive and negative selection, self-nonself discrimination and the roles of costimulation and anergy.

Mostardinha P P de Abreu F Vistulo FV

Scientific reports 20121025

It is still unclear whether the adaptive immune system can perform accurate self-nonself discrimination and what could influence its performance. Starting from simple cellular interaction rules we show that it is possible to achieve perfect self-nonself discrimination in a consistent framework provided positive and negative selection operate during repertoire education, and costimulation and anergy are also considered during T cell activation. In this theory T cell receptors diversity is require ...[more]

PMID: 23101027

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Project description:BackgroundThere is an increasing need for complex computational models to perform in silico experiments as an adjunct to in vitro and in vivo experiments in immunology. We introduce Microscopic Stochastic Immune System Simulator (MiStImm), an agent-based simulation tool, that is designed to study the self-nonself discrimination of the adaptive immune system. MiStImm can simulate some components of the humoral adaptive immune response, including T cells, B cells, antibodies, danger signals, interleukins, self cells, foreign antigens, and the interactions among them. The simulation starts after conception and progresses step by step (in time) driven by random simulation events. We also have provided tools to visualize and analyze the output of the simulation program.ResultsAs the first application of MiStImm, we simulated two different immune models, and then we compared performances of them in the mean of self-nonself discrimination. The first model is a so-called conventional immune model, and the second model is based on our earlier T-cell model, called "one-signal model", which is developed to resolve three important paradoxes of immunology. Our new T-cell model postulates that a dynamic steady state coupled system is formed through low-affinity complementary TCR-MHC interactions between T cells and host cells. The new model implies that a significant fraction of the naive polyclonal T cells is recruited into the first line of defense against an infection. Simulation experiments using MiStImm have shown that the computational realization of the new model shows real patterns. For example, the new model develops immune memory and it does not develop autoimmune reaction despite the hypothesized, enhanced TCR-MHC interaction between T cells and self cells. Simulations also demonstrated that our new model gives better results to overcome a critical primary infection answering the paradox "how can a tiny fraction of human genome effectively compete with a vastly larger pool of mutating pathogen DNA?"ConclusionThe outcomes of our in silico experiments, presented here, are supported by numerous clinical trial observations from the field of immunotherapy. We hope that our results will encourage investigations to make in vitro and in vivo experiments clarifying questions about self-nonself discrimination of the adaptive immune system. We also hope that MiStImm or some concept in it will be useful to other researchers who want to implement or compare other immune models.

Project description:Self/nonself discrimination is an essential feature for pathogen recognition and graft rejection and is a ubiquitous phenomenon in many organisms. Filamentous fungi, such as Neurospora crassa, provide a model for analyses of population genetics/evolution of self/nonself recognition loci due to their haploid nature, small genomes and excellent genetic/genomic resources. In N. crassa, nonself discrimination during vegetative growth is determined by 11 heterokaryon incompatibility (het) loci. Cell fusion between strains that differ in allelic specificity at any of these het loci triggers a rapid programmed cell death response.In this study, we evaluated the evolution, population genetics and selective mechanisms operating at a nonself recognition complex consisting of two closely linked loci, het-c (NCU03493) and pin-c (NCU03494). The genomic position of pin-c next to het-c is unique to Neurospora/Sordaria species, and originated by gene duplication after divergence from other species within the Sordariaceae. The het-c pin-c alleles in N. crassa are in severe linkage disequilibrium and consist of three haplotypes, het-c1/pin-c1, het-c2/pin-c2 and het-c3/pin-c3, which are equally frequent in population samples and exhibit trans-species polymorphisms. The absence of recombinant haplotypes is correlated with divergence of the het-c/pin-c intergenic sequence. Tests for positive and balancing selection at het-c and pin-c support the conclusion that both of these loci are under non-neutral balancing selection; other regions of both genes appear to be under positive selection. Our data show that the het-c2/pin-c2 haplotype emerged by a recombination event between the het-c1/pin-c1 and het-c3/pin-c3 approximately 3-12 million years ago.These results support models by which loci that confer nonself discrimination form by the association of polymorphic genes with genes containing HET domains. Distinct allele classes can emerge by recombination and positive selection and are subsequently maintained by balancing selection and divergence of intergenic sequence resulting in recombination blocks between haplotypes.

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Positive and negative selection, self-nonself discrimination and the roles of costimulation and anergy.

Publications

Positive and negative selection, self-nonself discrimination and the roles of costimulation and anergy.

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