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International Network in Theoretical Immunology

Final Report Summary - INTI (International Network in Theoretical Immunology)

1.1 Objectives of the project
The main aim of this proposal (INTI) is to set up an International Research Network in Theoretical Immunology that involves experimental and theoretical immunologists. This Network will create new collaborations and reinforce existing ones in order to develop a lasting and fruitful research cooperation between all the partners.
Other objectives of this proposal are:
1. Establish research collaborations between the experimental and theoretical immunologists of the network to provide immunology with a more quantitative basis.
2. Establish research collaborations between the different theoretical immunology groups to discuss, compare, test and validate different modelling approaches.
3. Train the new generation of (experimental and theoretical) immunologists, with the aim to exchange postgraduate students and research fellows, so that they benefit from the broader knowledge, skills and tools provided by the Network.
A final objective of the Network is to develop, by means of the Staff Exchange Scheme, four long-term directions for modelling in immunology. In particular,
(i) To develop stochastic models for the motion of pathogens and of cells of the immune system.
(ii) To develop mathematical and computational models to help us understand how the immune system maintains its diversity of millions of lymphocyte populations.
(iii) To develop stochastic models of T cell and B cell maturation.
(iv) To develop models of autoimmunity. The knowledge developed and exchanged in this Programme will be essential for understanding and manipulating immune responses to infectious organisms.

1.2 Summary overview of results
1. T cell receptor antigen recognition and activation (Theme 1).
T cells recognise antigen in the form of a peptide complex with an MHC molecule (pMHC). In order to trigger an immune response to an invading micro-organism, while avoiding a response to self, the interaction between the T cell receptor (TCR) and the pMHC must be both highly specific and highly sensitive. This is achieved by molecular interactions at three different levels: TCR binding to pMHC, activation of cellular signalling cascades and gene expression. On this theme, we have: H developed models of receptor-ligand interactions at cell-cell interfaces, developed stochastic models of small clusters of T cell receptor (TCR) binding to its ligand, developed models of TCR diffusing on the cell membrane, developed mathematical models that account for TCR conformational change, and developed models of TCR binding that can explain the affinity threshold hypothesis.

2. Homeostasis and control of lymphocyte proliferation and death (Theme 2).
Maintaining constant numbers of na¨ive and memory T lymphocytes throughout adult life is a central feature of the immune system. It depends on steady state dynamics of input into the T cell pool from the thymus, T cell proliferation in response to antigen, as well as antigen-independent “homeostatic” proliferation, terminal differentiation and programmed cell death (apoptosis). At the same time, diversity of antigen specific clones must be maintained, both in the na¨ive pool and, particularly, in the T cell peripheral pool required for long term immunological memory. On this theme, we have: developed models of branching processes to describe cell division, developed models of inference to obtain parameter values of T cell death rates and proliferation rates during homeostasis,

2.developed mathematical models to quantify the contribution of thymus output and peripheral na¨ive T cell division to the maintenance of T cells in mice and men, and developed models of quorum sensing for CD4+ T cells.

3. Lymphocyte differentiation (Theme 3).
The rapid and extended proliferation that follows recognition of antigen by na¨ive T cells in the lymph nodes is also accompanied by differentiation and the acquisition of effector and/or memory phenotypes. This has parallels with developmental processes; the response of T cells appears to have a strong genetic programming component, but cell fates are also clearly influenced by environmental factors such as cytokine milieu and signals derived from direct interactions with other cell types, particularly professional antigen presenting cells (APCs). On this theme, we have: developed stochastic models to understand intracellular competition for fates in the immune system, developed new models with explicit connection between B cell and T cell differentiation, apoptosis and cell division and germinal centre zone migration, and developed new models of differentiation of naive cells into memory/experience T cells along the regulatory, Th1, Th2, and Th17 subtypes, both in terms of the intrinsic gene network and the interactions the cells make among them.

4. Cell-cell interactions (Theme 4).
Upon challenge with cognate antigen, T cells pass through a phase where they have long-lasting contacts with dendritic cells (DCs). Recent developments in in vivo imaging, that allow the movement of labelled cells in lymph nodes, and contacts between them, to be tracked and recorded, as well as opening up new areas for Mathematical Immunology, throw up practical questions on a daily basis. For example, imaging experiments typically last 30 to 60 minutes due to current technical constraints. Furthermore, only a limited field of view can be imaged, thus T cell-DC conjugates regularly move into and out of the imaged volume. This means that an interaction that is observed for several minutes, but whose initiation or termination was not observed, could in reality last many hours. If a number of T cell-DC interactions lasting tens of minutes are observed in an imaging experiment limited to less than an hour, what can be deduced about the possibility of interactions lasting for hours or days? Providing an answer to this mathematical challenge will be one of the objectives of this programme. On this theme, we have: developed stochastic models of encounters between cells presenting pathogen-derived peptides (DCs), developed and established new collaborations with immunologist Prof. Bousso (Pasteur Institute, France), developed new models that include the observed phenomena of accumulation of dendritic cells around the lymph node entrances, and into networks known as conduit systems, and developed mathematical models of chemotactic migration of T cells that allow the detection of rare antigens.