New imaging techniques:
challenges for experimental and theoretical immunology

[c]
  • Monday 24 September. University House

    • coffee
    • 9:30-9:45

      Bronek Wedzicha

      Inauguration

    • 9:45-10:30

      Robin Callard (UCL)

      Modelling Images of the Immune system

      The immune system is made up from a very complex set of interconnected cells and molecules that may be separated in both space and time. Making the right response to an invading pathogen depends on integrating gene and signalling networks with communication networks between many different cells and cell types. This includes migration of signalling molecules to different compartments within the cell and migration of activated cells to specific anatomical sites where they interact with other cell types. These properties make the immune system very difficult to study experimentally and most modern immunology concentrates on characterizing the properties of individual cells and molecules rather than the system as a whole. In this talk I will describe the main features of the immune system and then use models of T cell homeostasis and T helper cell differentiation as examples of how imaging techniques can be combined with mathematical modeling to gain a better understanding of how the immune system works.
    • coffee
    • 11:00-11:45

      Sheena Cruickshank (University of Manchester)

      Epithelial Cell Interactions in the Gut in Inflammation and Infection

      The immunology of the gut is complex and is still not well understood. The gut has a high antigenic load and must distinguish between good (food or commensal bacteria) and bad antigens (pathogens). The epithelial cells, that line the gut, form the first point of contact with many of the antigens in the gut. The epithelial cells can recognise and distinguish gut antigens and interact with immune cells. The immune response is shaped by a interweaving network of cell:cell interactions that will ultimately lead to containment or eradication of a pathogen. As the epithelial cell is likely to be at the initiation of this cascade, qualitative and quantitative differences in epithelial cell interactions may direct the immune response in the gut.
    • 11:45-12:30

      Carmen Molina-París (Leeds)

      Peripheral T cell repertoire maintenance

      A healthy immune system requires a T cell population that responds promptly to foreign antigen. This is achieved by using a variety of self-peptides to (i) select a receptor repertoire in the thymus and (ii) keep naive T cells alive and ready for action in the periphery. In this talk I will present a stochastic mathematical model to study T cell repertoire diversity maintenance. The model incorporates the concept of survival stimuli emanating from self antigen presenting cells. I will show that in the mean field approximation clonotype extinction is guaranteed and compute extinction times of T cell clonotypes without thymic input. I will introduce the concept of the mean niche overlap and make use of the quasi-stationary distribution to compute average clonotype numbers for different values of the niche overlap.
    • catered lunch
    • 2:00-2:45

      Paul Garside (Strathclyde)

      Imaging immune responses in real time in vivo

      In vivo analysis of the mechanisms and requirements for the induction of tolerance or immunity is the most instructive way to define these processes and will be critical for the development of vaccines and immunotherapy. However, this approach has been hampered in the past by two major problems. Firstly, the low frequency of antigen-specific precursor lymphocytes in a normal animal has precluded direct examination of the cells involved and secondly the analysis techniques required to monitor real-time interactions of cells in immune tissues have not been available. With regard to the first obstacle, we and others have developed novel techniques to track antigen-specific T and B lymphocytes in vivo. Despite this, these approaches are still limited by conventional analysis systems to give a "snapshot" of the immune response in vivo. However, the recent development of multiphoton scaning laser microscopy, with the ability to penetrate directly into tissues, allows visualisation of cells within intact tissue in vivo. We have therefore combined our expertise in tracking immune cells in vivo with that in multiphoton microscopy to develop systems to analyse the early cellular and molecular events underlying immunological priming and tolerance in real time directly in vivo.
    • 2:45-3:30

      Marc Thilo Figge (Frankfurt Institute for Advanced Studies)

      Bridging the gap from single cells to organized cell systems

      This talk represents an overview of mathematical methods that are applied in order to investigate biological systems. Several examples will be touched ranging from two interacting cells and the associated molecular organization during the formation of the immunological synapse to cellular organizations such as the germinal center reaction and growing tumors. Finally, the capability of these methods to analyze two-photon microscopy data of cellular systems will be demonstrated and discussed.
    • tea
    • 4:00-5:00 discussion
    • 8:00- Dinner at Casa Mia, Millennium square
  • Tuesday 25 September. Centenary gallery,Parkinson building

    • coffee
    • 9:45-10:30

      Salvatore Valitutti (INSERM Toulouse)

      Inter-cellular information transfer at the immunological synapse

      We apply three-dimensional confocal microscopy and time lapse video-microscopy techniques to visualize molecular dynamics at the immunological synapse (IS). The major contribution of our research team to the field during the last few years has been to contribute to define the biological function of the IS. We propose that the IS has no specific function in T cell activation, on the contrary it is the "manifestation" of the inter-cellular communication occurring during T cell/APC cognate interactions. Our results show that: i) the large-scale molecular clustering and segregation characteristic of a mature IS is not required for productive TCR triggering and for T cell activation (indeed some responses such as cytotoxicity can occur in the absence of mature IS formation); ii) T cells form different types of synapses depending on the strength and quality of antigenic stimulation; iii) synapses can be interrupted and re-formed while T cells add-up the interrupted signals; iv) synapses are not static structures, on the contrary, they are dynamic and adaptable. This flexibility allows T cells to communicate with multiple APC simultaneously and polarize their secretory machinery towards the APC offering, at any given time, the best mix of ligands to engage TCR and accessory molecules. Recent results of our research team further support the notion that IS are dynamic and adaptable structures. We showed that: i) cytotoxic T lymphocytes (CTL) can kill multiple targets simultaneously by rapidly addressing lytic granules towards different adjacent cells; ii) regulatory T lymphocytes (Treg) inhibit the dynamics of the Golgi apparatus in effector T cells.
    • coffee
    • 11:00-11:45

      Andrew Yates (Emory)

      Getting the measure of T cell behaviour in vivo

      I'll discuss two in vivo assays using the LCMV mouse model we've been using at Emory and their analysis using mathematical models. One measures CTL killing rates, and I'll show how the models allow us to measure differences in the rates at which effector and memory CTL survey and kill targets, and the differences between dominant and subdominant epitope responses. The other is a recent experiment that strongly suggests that T cell memory compartment is semi-flexible in its capacity; that is, new infections result in both expansion of total memory CD8 T cell numbers and some attrition of incumbent, non- related specificities. If time permits I'll suggest how the interpretation of the data from both assays might be improved using spatial visualisation tools.
    • 11:45-12:30
    • Daniel Coombs (University of British Columbia)

      Directions for studying the mobility of cell-surface proteins

      The mobility of cell surface proteins is a key component of many cellular processes, including, for example, the formation of the immune synapse. Popular techniques for studying this are fluorescence recovery after photobleaching (FRAP) and single particle tracking (SPT). I will describe these methods, and indicate how theoretical work can improve parameter estimation. In particular I will outline application of FRAP to measuring binding kinetics of proteins restricted to cell surfaces, and discuss directions for improving analysis of SPT data.
    • catered lunch
    • 2:00-3:00 discussion
    • tea
    • 3:30-5:00 discussion
  • Wednesday 26 September. University House

    • coffee
    • 9:45-10:30

      Benedict Seddon (NIMR)

      The challenges for modeling T cell homeostasis

      The peripheral T cell compartment is maintained at a remarkable constant size and composition throughout life, in spite of constant cell production and death. The factors and signals that regulate this homeostasis are well characterised at a qualitative level. However, the quantitative importance of these signals for the different T cell subsets and their relative importance in regulating key homeostatic death and cell division events remains unclear. The key issues and points of uncertainty in trying to understand the homeostatic processes will be discussed as will the contribution mathematical modeling may play in aiding our understanding. A simple modeling approach used to understand the most basic homeostatic responses will be presented and discussed.
    • coffee
    • 11:00-11:45

      Keng-Hwee Chiam (IHPC Singapore)

      Computational modeling of cell adhesion and migration

      Leukocyte recruitment, lymphocyte recirculation, and monocyte trafficking all require adhesion and migration through the bloodstream. We discuss computational models to study the adhesion and migration of leukocytes. In particular, we focus on the mechanical aspects of this process, and numerically compute the deformation of a migrating leukocyte, which is the result of the competing forces induced by the shear flow of the bloodstream as well as adhesive forces between the leukocyte and the vascular endothelium mediated by the integrin and selectin families of molecules. In particular, we show that the length of the cell membrane that is adhered to the substrate can be expressed in a very simple relation involving only the product of the inverse of the cells capillary number and the distance that the cell has migrated. We also show that this relation may be exploited in determining a leukocyte's cytoplasmic viscosity in terms of mechanical quantities such as adhered length and distance migrated. Finally, we discuss the implications of these results in the context of leukocyte capillary plugging.
    • 11:45-12:30

      Gib Bogle (University of Auckland)

      Building a model of T cell motility, activation and proliferation

      Gib Bogle and Rod Dunbar
      Spatial factors influence T cell activation in several ways. Initial contact with and stimulation by DC bearing cognate antigen follows from a T cell's random roaming behaviour in the lymph node paracortex. Stimulation causes a T cell to secrete cytokines, contributing to fields of cytokine concentration. As they move T cells experience a changing cytokine environment that modulates their activation and proliferation. Swarming and clustering may also generate additional positive feedback.
      We are constructing a model to simulate a large number of T cells over a period of 5 - 10 days as a cognate subset are activated by DC and proliferate. The agent-based model accounts for T cell motility and DC encounters, for IL2 secretion, consumption and diffusion, and for T cell internal state evolution under the influence of DC stimulation and IL2 exposure.
    • catered lunch
    • 2:00-3:00 discussion

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