Kennedy Lecture Theatre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH
5th March 2010
8:45 – 9:20 Registration 9:20 – 9:30 Introduction by the Chair: Dr Oliver Garden, The Royal Veterinary College, London, UK 9:30 – 10:15 The influence of the tumour environment on regulatory T cells Professor Julian Dyson, Department of Immunology, Division of Medicine, Imperial College London, UK Regulatory T cells function to dampen pathogenic immune responses and were originally identified by their role in preventing autoimmunity. Tumour antigens are also self-antigens and tumour specific immunity can be compromised by the activity of regulatory T cells. To investigate the influence of the tumour environment on regulatory T cells, we have developed models in which tumour specific or non-specific regulatory T cells are transferred into tumour bearing hosts. Using this approach, we have examined regulatory T cell localization and expansion, the role of tumour derived TGFb, Foxp3 stability, development of inducible regulatory T cells and the impact of vaccination. 10:15 – 11:00 Harnessing regulatory T cells for therapy in rheumatoid arthritis Professor Michael Ehrenstein, Professor of Experimental Rheumatology, Windeyer Institute, University College London, UK Regulatory T cells (T reg) from patients with RA have defective suppressor function. Following anti-TNF-alpha (infliximab) treatment, Treg from RA patients appear to regain their suppressive function, but only in those individuals who respond to therapy. However, infliximab, rather than restoring the defect in Treg, induces the differentiation of a distinct and potent population of CD62L- Treg from responder T cells. The suppressive capability of these CD62L- Tregs is dependent upon TGF-beta and IL-10, unlike Tregs from healthy individuals which suppressed through cytokine independent mechanisms. Our recent results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA, and may represent a target for therapy to induce long lasting remission. 11:00- 11:10 Speakers’ photo 11:10 – 11:30 Mid-morning break 11:30 – 12:15 Induction and function of antigen specific Tr1 cells in human diseases
Professor Maria Grazia Roncarolo, San Raffaele Telethon Institutefor Gene Therapy (HSR-TIGET), Italy 12:15-13:00: Oral presentations of selected abstracts 13:00-14: 00 Lunch and Networking 14: 00 - 15:00 Keynote address: Regulatory T cell control of pathogenic and effector T cells - implications for cancer and autoimmunity Professor Kingston Mills, Professor of Experimental Immunology and Head School of Biochemistry and Immunology, Trinity College Dublin 15:00-15:30: Afternoon coffee / tea / juice / cake break 15: 30-16:15 Talk title to be confirmed Professor Daniel Altmann, Professor of Immunology/Deputy Head of Department in the Department of Infectious Diseases and Immunity, Imperial College London, UK 16: 15-17:00 Understanding the mechanisms of conversion of regulatory T cells to IL-17-producing T cells during inflammation Professor Giovanna Lombardi, Division of Medicine, King’s College London, UK Naturally arising CD4+CD25+ regulatory T cells play a pivotal role in the prevention of autoimmunity. Strategies are under development to establish ways of expanding Tregs in vitro for clinical use to achieve tolerance in autoimmunity and transplantation. In the last few years, we have built a platform of data in murine models which support the hypothesis that Tregs are very efficient in inducing allograft survival. However, we and others have shown recently that human Tregs under inflammatory conditions are prone to conversion to proinflammatory Th17 cells, which have been shown to be key effector cells in autoimmune responses and in graft rejection. In this study we have investigated the mechanisms of human Treg to Th17 conversion. We have shown that the major cytokine involved in the conversion of human Tregs to Th17 in vitro is IL-1 and that this effect is mediated by a shift from functional activation of STAT5 to STAT3. This conversion was critically dependent on STAT3 as Tregs from human patients with dominant-negative mutations in STAT3 did not produce IL-17 in response to IL-1. Despite the role of IL-6 in activating STAT3, this cytokine did not convert Tregs to Th17. Analysis of SOCS proteins demonstrate that IL-1 but not IL-6 could promote a permissive enviroment for SOCS protein. Our data provide mechanistic insight into the actions of IL-1 induction of Treg to Th17 conversion. Different strategies are now under investigation to identify molecular difference between Tregs pre- and post-conversion, to prevent their subversion. The success of these strategies will influence the design of the first trial in which Tregs will be used in organ transplantation, where inflammation is present by avoiding the risk of conversion to IL-17 producing cells. 1 7:00-17:15 Chairman’s summing up
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