BBSRC MATSYB network

I2M: Immunology, Imaging and Modelling

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The ability to track parasites and cells in vivo in intact tissues using novel imaging techniques is poised to enable important and challenging questions to be addressed. In particular, recent advances in two-photon microscopy and cell labelling have made it possible to observe cell interactions in real time and in vivo. This approach provides a significant step forward in experimental immunology. However, our understanding of the complex four dimensional behaviour (space and time) of B and T cells has remained limited. The development of mathematical models to analyse and simulate these cell interactions is essential to fully account for the complexity of the immune responses. This initiative seeks to open up a new pathway making use of mathematical modelling to study the dynamic interactions of immune cells and pathogens. Understanding and quantifying how the immune system works poses a ma jor scientific challenge of vital importance to the immunology and medical research community. This initiative combines concepts from immunology with mathematics, physics and chemistry to tackle this challenge.

The first meeting of the network: 10 Jan 2008, School of Mathematics at the University of Leeds.
The second meeting of the network: 21 May 2008, Institute of Child Health, University College London.
  • Location

    Room A, Wellcome Trust Building

    Transport

    How to get to Institute of Child Health

    Programme

  • 10:00-10:45  

    Hugo van den Berg

    Warwick

    Dynamic TCR crossreactivity through coreceptor tuning

    The functional sensitivity of a T cell to peptide-MHC ligands is a dynamic quantity which is continually being adjusted by immunoregulatory mechanisms. This process is vital in the maintenance of a diverse repertoire, avoidance of autoimmunity, and the ability to mount an efficacious immune response against a pathogenic challenge. There are various modulatory mechanisms which, acting in concert, alter a T cell's activation threshold through costimulation and its TCR's affinity and triggering threshold through coreceptor tuning. Various mechanism have been proposed for the effect of the coreceptor CD8 on TCR sensitivity. We have studied the quantitative importance of each mechanism, combining experiments and theoretical analysis. These studies suggest that the TCR repertoire resolves the paradox of attaining sufficient functional diversity with a comparatively modest number of clonotypes, whilst avoiding autoimmunity, by means of a novel mechanism which we call "focussed specificity". On this theory, each TCR is potentially crossreactive to many ligands, but will at any one time have a large functional sensitivity to only a few of them. Dynamic specifity focussing would constitute the T cell counterpart to affinity maturation in B cell immunity.
  • 11:00-11:45  

    Graham Anderson

    MRC Centre for Immune Regulation, University of Birmingham, B15 2TT

    Regulation of T-cell Development In The Thymus

    The development of functionally competent antigen-specific T-cells occurs within the thymus. Blood-borne immature T-cell progenitors are recruited to the thymus by a chemotactic process, involving CCR7- CCL21 and CCR9-CCL25 interactions. Development of T-cell progenitors within the thymus involves a complex series of steps including proliferation, antigen receptor gene rearrangement, differentiation, and selection of T-cell receptor specificities to ensure the production of a self-tolerant T-cell repertoire. It is clear that all the appropriate queues that drive T-cell development are provided by stromal cells that make up the thymic microenvironment. These cells include cortical and medullary epithelial cells, dendritic cells, macrophages and mesenchymal fibroblasts. To gain a better understanding of how thymic stromal cells regulate T-cell development, we have established in vitro techniques based on the disaggregation and reaggregation of thymic tissue. This allows us to form three-dimensional thymic structures in vitro from defined thymocyte and stromal cell subsets, enabling the analysis of specific developmental events in a synchronous fashion. Data presented will summarise our use of this system to study the positive and negative selection of the T-cell repertoire, as well as the processes driving thymic epithelial cell development.
  • 11:45-12:30 discussion
  • 12:30-2:00 lunch
  • 2:00-2:45

    Rachel Norman

    Head of the Mathematics and Statistics Group Department of Computing Science and Mathematics University of Stirling

    Mathematical Models of Disease Systems: an Applied Example and a Theoretical Approach.

    The talk will consist of two parts. In the first I will present work which has been carried out for a number of years on modelling Louping ill virus. This is a tick borne infection of sheep and grouse which is of economic importance in the Scottish Highlands. There are a number of different hosts involved in this system, some which are simply hosts for the ticks (e.g. deer) and some which are involved in disease transmission (e.g. mountain hares). In this part of the talk we will look how we might control the disease by manipulating the host densities on different estates. In the second part of the talk I will introduce a new theoretical approach which I have been working on with colleagues in Computing Science. We have utilised a technique which allows us to write down rules of individual behaviour and then to scale up to behaviour at the population level. I will illustrate this by looking at transmission in a disease system, but this could easily be applied to a number of different systems, including immunological ones.
  • 3:00-4:30 discussion (proposals, FP7, web of network, INI programme, etc.)

Objectives of the I2M Research Network

  • Develop the links and a common language between immunologists, mathematicians, computer scientists, physicists and engineers to address this new challenge in systems biology.
  • Develop a theoretical framework to model the behaviour of cellular immune responses, learning from advances in stochastic
  • Develop a computational framework to simulate and analyse the dynamical behaviour of cellular immune responses in different immunological conditions, learning from advances in systems and control engineering.
  • Assess, test and validate the proposed frameworks with experimental data.
  • Transfer ideas, experimental techniques, models and insight from the biological, mathematical, physical, engineering and computational communities to industry and conversely introduce ideas in these scientific communities from industrial systems engineering experience.

Modelling T-cell and antigen presenting cell (APC) interactions

Modelling B-cell responses

Modelling outcomes of infection

 

Identification of antigen specific (red), IFNgamma producing (green) T lymphocytes in B cell follicles (blue) in lymph nodes during induction of Th1 immune responses in vivo.
(from Smith KM, Brewer JM, Rush CM, Riley J, Garside P. In vivo generated Th1 cells can migrate to B cell follicles to support B cell responses
J Immunol. 173 1640

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html PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" "http://www.w3.org/TR/html4/transitional.dtd"> Immunology Network

New imaging techniques:
challenges for experimental and theoretical immunology

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The immunet research network has been set up to develop a common language between immunologists, mathematicians, computer scientists, physicists and engineers.

The immune system is one of the most fascinating and complex multiscale systems imaginable. Recent advances in two-photon microscopy and cell labelling have made it possible to track parasites and cells in vivo and to observe cell interactions in real time and in vivo. But, while these techniques have revolutionised the science of cellular immunology, theoretical and computational modelling are essential to go beyond qualitative descriptions and quantify the cellular immune response during health and disease.

Immunology has traditionally been a qualitative science describing the cellular and molecular components of the immune system and their functions. Quantifying the interactions of these individual parts is a major challenge of vital importance to the immunological and medical research communities. Combining expertise and concepts from different disciplines will help us to develop models to interpret experimental data, to resolve controversies, and to suggest novel experiments allowing for more conclusive and more quantitative interpretations.
The theoretical-experimental immunology meeting funded by the University of Leeds will take place from the 24th of september (Monday) to the 26th of september (Wednesday).

 

Identification of antigen specific (red), IFNgamma producing (green) T lymphocytes in B cell follicles (blue) in lymph nodes during induction of Th1 immune responses in vivo.
(from Smith KM, Brewer JM, Rush CM, Riley J, Garside P. In vivo generated Th1 cells can migrate to B cell follicles to support B cell responses
J Immunol. 173 1640

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