Timothy Tree, PhD
Tel: +44 (0) 207 188 1182
Fax: +44 (0) 207 188 3385
The role of immune regulation in human health and disease.
In recent years there has been a considerable expansion in our understanding of the physiology of peripheral T cell immune regulation. This has led to the delineation of several different types of regulatory T cells (Tregs); major examples include T cells co- FoxP3 expressing CD4+ CD25+ Tregs and Tr1 cells producing large amounts of IL-10 and TGF-β. Our laboratory focuses on the characterization of these and recently identified novel populations of Tregs in the context of the prototypical human T cell mediated autoimmune disease, type 1 diabetes (T1D). Specifically our research addresses three main questions:
(i) What T cell mediated mechanisms are involved in regulating potentially pathogenic autoreactive T cells in healthy individuals?
(ii) Does a numerical or functional deficiency in Tregs contribute to the development of autoimmune diseases such as T1D?
These studies will promote our understanding of the immune processes that lead to pathological autoimmunity, and enable the development of tools to promote the study of a third question, namely:
(iii) Can regulatory mechanisms can be promoted in diabetes-prone or islet transplanted individuals through immunotherapeutic interventions.
The approach of our laboratory has been to focus on human, islet-specific immune regulation in states of both health and disease. In doing so, we have identified a functional defect in the action of CD4+CD25+ Tregs in individuals with T1D and uncovered two hitherto undefined T-reg populations of importance to this field namely; islet specific IL-10 secreting (ISIS) Tregs and HLA-DQ restricted insulin specific Tregs.
We are now involved in a set of studies to understand the genetic and molecular basis of defective Treg function associated with T1D and develop clinically applicable strategies to improve either the number or functional capacity of Tregs in diabetes prone individuals.
Tree TI, Lawson J, Edwards H, Skowera A, Arif S, Roep BO, Peakman M: Naturally arising human CD4 T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression. Diabetes 59:1451-1460, 2010
Huurman VA, Velthuis JH, Hilbrands R, Tree TI, Gillard P, van der Meer-Prins PM, Duinkerken G, Pinkse GG, Keymeulen B, Roelen DL, Claas FH, Pipeleers DG, Roep BO: Allograft-specific cytokine profiles associate with clinical outcome after islet cell transplantation. Am J Transplant 9:382-388, 2009
Lawson JM, Tremble J, Dayan C, Beyan H, Leslie RD, Peakman M, Tree TI: Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol 154:353-359, 2008
Tree, T.I., Duinkerken, G., Willemen, S., de Vries, R.R., and Roep, B.O. 2004. HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65. Diabetes 53:1692-1699.
Lindley, S., Dayan, C.M., Bishop, A., Roep, B.O., Peakman, M., and Tree, T.I. 2005. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 54:92-99.
*Tree, T.I., Arif, S., Astill, T.P., Tremble, J.M., Bishop, A.J., Dayan, C.M., Roep, B.O., and Peakman, M. 2004. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 113:451-463. (* joint 1st author)