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- 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
-
- 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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