Immunology and Diabetes - Immunology Laboratory headed by Professor Tom Kay
Immunology Laboratory headed by Professor Tom Kay
Research Overview
In type 1 diabetes, insulin-producing beta cells (arranged in clusters called islets) are destroyed by immune mechanisms. The major immune cell type involved is the CD8+ cytotoxic T lymphocyte (CTL) that directly recognises short peptides derived from proteins like insulin presented by major histocompatibility complex class I proteins on the surface of beta cells. We study the precise mechanisms by which T cells destroy beta cells, and test ways to prevent this from happening. Much of our work is based on the NOD mouse model that develops diabetes in a similar manner to humans. We also have several transgenic mice that express particular T-cell receptors that are able to cause rapid diabetes. We use these mice, and our expertise in flow cytometry, immunohistochemistry and molecular biology, to study the role that cytokines, death-receptor molecules and perforin/granzymes play in the development of diabetes. The major questions we are studying are the use of immune tolerance to insulin as a way of arresting diabetes and also CTL differentiate into fully effective cytotoxic T cells.
Research Themes
Role of cytokines and death receptors in beta cell destruction and type 1 diabetes
Role of cytotoxic T cells in human type 1 diabetes
Tolerance to beta cell antigens recognised by CD8-positive T cells
Staff
Professor Tom Kay
Dr Bala Krishnamurthy
Dr Kate Graham
Dr Tom Loudovaris
Gaurang Jhala
Rochelle Ayala-Perez
Lina Mariana
Jonathan Chee
Hong Sheng
Caroline McBride
Yue Li
Publication Highlights
Krishnamurthy B, Dudek NL, McKenzie MD, Purcell AW, Brooks AG, Gellert S, Colman PG, Harrison LC, Lew AM, Thomas HE, Kay TWH (2006) Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 116:3258-65.
Chong MMW, Cornish AL, Darwiche R, Stanley EG, Purton JF, Godfrey DI, Hilton DJ, Starr R Alexander WS, Kay TWH (2003) Suppressor of Cytokine Signaling-1 is a Critical Regulator of Interleukin-7-Dependent CD8+ T cell Differentiation. Immunity 18:475-8.
Chong MM, Chen Y, Darwiche R, Dudek NL, Irawaty W, Santamaria P, Allison J, Kay TWH, Thomas HE (2004) Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction. J Immunol 172:5714-21.
Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP, Kay TWH, Rossjohn J, Falk BA, Nepom GT, Purcell AW (2005) The insulin A-chain epitope recognized by human T-cells is post-translationally modified. J Exp Med 202:1191-7.
Thomas HE, Darwiche R, Corbett JA, Kay TWH (2002) Interleukin-1 and interferon-gamma-induced pancreatic beta cell dysfunction is mediated by beta cell nitric oxide production. Diabetes 51:311-16
Krishnamurthy B, Mariana L, Gellert SA, Colman P, Harrison LC, Lew AM, Santamaria P, Thomas HE, Kay TWH. Autoimmunity to both proinsulin and IGRP is required for diabetes in nonobese diabetic 8.3 TCR transgenic mice. J Immunol 2008; 180: 4458-4464
McKenzie MD, Carrington EM, Kaufmann T, Strasser A, Huang DCS, Kay TWH, Allison J, Thomas HE. Pro-apoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic b cells. Diabetes 2008; 57: 1284-92
Angstetra E, Graham KL, Emmett S, Dudek NL, Darwiche R, Ayala-Perez R, Allison J, Santamaria P, Kay TWH, Thomas HE. In vivo effects of cytokines on pancreatic beta-cells in models of type 1 diabetes dependent on CD4+ T lymphocytes. Immunol Cell Biol, 2009: 87:178-85 (2009)
Kay TWH, Krishnamurthy B, Brodnicki TC, Mannering SI. Insulin teaches a new lesson in tolerance. The EMBO Journal 28(18):2687-8 (2009)
McKenzie MD, Jamieson E, Jansen ES, Scott CL, Huang DCS, Bouillet P, Allison J, Kay TWH, Strasser A, Thomas HE. Glucose induces pancreatic islet cell apoptosis that requires the BH3-only proteins Bim and Puma and multi-BH domain protein Bax. Diabetes, in press (2009)
Thomas HE, Graham KL, Angstetra E, McKenzie MD, Dudek NL, Kay TW. Interferon signalling in pancreatic beta cells. Frontiers in Bioscience 14:644-656 (2009)
Thomas HE, McKenzie MD, Angstetra E, Campbell PD, Kay TW. Beta cell apoptosis in diabetes. Apoptosis 14:1389-1404 (2009)