A Meeting summary : Competition, Regulation and Feedback in the Immune System. Organiser - Nigel Burroughs. Thirty five mathematicians and immunologists converged on the Mathematics Institute in the University of Warwick (UK) to attend a 3 day meeting in March on Competition, Regulation and Feedback in the Immune System. A variety of issues were presented both from an experimental and a modelling perspective. Antonio Freitas opened the meeting with experiments on the regulation of the peripheral pool of B cells, highlighting the selection for diversity, ie in competition with a normal repertoire transgenic B-cells are under represented in the periphery relative to a partition in the bone marrow. Benedita Rocha complemented this data with experiments on the regulation of the T-cell pool, demonstrating that the memory and naive pools are regulated independently. Further the peripheral pool cannot be reconstructed by proliferation alone. A random substitution model of naive cells by those from the thymus was suggested as a method to retain diversity. However, a model with active diversity driven selection, as seen in the loss of transgenic B-cells in competition, suggests the need for competition between lymphocytes. Such a model was presented by Rob de Boer, who used niche competition between T-cells and TCR cross reactivity to explain these observations. The identity of these niches is unknown, although self epitopes are a possibility. Clearly the size of the repertoire is determined by the number of niches. Arne Akbar moved the focus from birth processes to death, and the competition for rescue signals from apoptosis (programmed cell death). Two means of apoptosis - cytokine deprivation and activation induced death - were outlined, and a demonstration of apoptosis in human skin tissue (of willing subjects) was presented, where a significant, but small (<10%) proportion of lymphocytes stain for apoptotic markers. Apoptosis is used to remove lymphocytes after the clearance of a virus; however it is not clear how this process is regulated as a whole or as an ecological process, although a number of signalling molecules and genes have been elucidated. This feedback by up/down regulation of rescue genes (bcl) and feedback through accessory molecules (CD28,B7) presented by Peter Lane provided a large body of examples as a backdrop to the generic positive/negative feedback models presented by Lee Segel, in his quest to resolve conflicting goals. A move to a molecular perspective was initiated by Salvatore Valitutti in a fascinating presentation on signalling in T-cells when conjugated to a target cell. Signalling in T-cells is a complex process that takes hours; sustained Ca signalling being required for responses such as cytokine secretion and proliferation. Serial T-cell receptor engagement is probably responsible for sustained signalling, and surface down regulation and destruction of the T-cell receptor responsible for its extinction. A video presentation by Christoph Wulfing of beads moving to the T-cell-target interface from throughout the rest of the T-cell surface demonstrated that the T-cell surface is in active dynamic motion during the T-cell target interaction. These talks raise questions about the validity of simple ecological modelling to immune system dynamics. An attempt at incorporating these additional complexities was made by Nigel Burroughs, presenting models with T-cell receptor and Il2 receptor up/down regulation under T-cell target interactions. T-cell competition was reproduced by these phenotype adaptation models. An alternative approach was taken by A.Noest, who approached the problem of immune system regulation from an engineering perspective by optimising for signalling at an individual cell level. Although the validity of such an assumption was questioned (since the immune system tolerates auto-reactive cells) this raised an interesting point - how is an immune response optimised, especially from the perspective of signals in the population of immune cells? Other topics included the missing self hypothesis in Natural Killer Cells with dynamic surface modulation of inhibitory receptors on these cells indicating that self is learnt on an individual cell basis (Petter Hoglund), models of differential rates of signaling to explain altered peptide observations (Andrew George), escape mechanisms in LCMV (Paul Klenerman) with exhaustion modelling (Can Kesmir), viral evasion mechanisms in vaccinia virus (Julian Symons), models of immune memory (Rustom Antia) and modelling of gene rearrangements in T-cells (Ramit Mehr). A final session on viral dynamics allowed HIV modelling to appear (Martin Nowak, Angela McLean), with a final return to the theme of diversity by David Rand on the selection of viral diversity by altered peptide antagonism. This meeting has put the University of Warwick and its Mathematics in Medicine Initiative on the map, not only for mathematical biology but for a keenness to open bottles of wine.

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