Laboratory Head
A/Professor Robyn Slattery
Phone: (03) 9903 0075
Email: Robyn.slattery@monash.edu
Department of Immunology
Monash University
Level 1, AMREP Building
89 Commercial Road
Melbourne Victoria 3004
AUSTRALIA
Staff List
Post-doctoral Fellow
Alexandra Ziegler
PhD students
Abhirup Jayasimhan
Research interests
Type 1 diabetes (T1D) in both humans and non-obese diabetic (NOD) mice results from T cell mediated autoimmune destruction of insulin producing pancreatic ß cells. Our group combines an immunopathological approach with genetic linkage studies to understand how autoreactive T cells are selected in the thymus, how they are activated in the pancreatic LN, and how they cause beta cell destruction resulting in loss of insulin production, and the development of T1D. Linkage studies, and more recently Genome Wide Association studies (GWAS), have identified more than 50 non-HLA regions to be associated with T1D. Our research group is interested in studying two of the susceptibility regions identified through linkage studies Idd1 (the MHC) and Idd13 (identified by our group to contain ß2M), in association with the pathogenic role of autoreactive killer T cells. Our lab is also interested in the analysis of a number of SNPs associated with human T1D for which the gene in T1D prone mice is associated with autoreactivity in B cells.
Idd1
Our group utilizes the cre/lox recombination system in NOD mice to understand the role of the MHC genes in diabetes. This system allows us to remove MHC genes from specific tissues while leaving these genes expressed normally in other tissues. We have thus far created a panel of cre NOD mice that allow us to delete MHC expression from either the target beta cells, or different subpopulations of the immune system. Using these mice we have been able to determine that CD8 T cells directly interact with MHC class I on the surface of beta cells in order to mediate their killing. Again using the cre lox system to delete MHC class I expression from class II positive professional antigen presenting cells (pAPCs) we demonstrated the importance of pAPCs in activating the killer CD8 T cells. However, surprisingly we found there was an infiltrate around the ducts of the islets that preceded activation of the killer CD8 T cells, and we are currently using the cre lox system to determine the specificity of these cells and their role in initiating T1D.
Idd13
Using allelic reconstitution by transgenic rescue we showed that NOD mice expressing the ß2Ma allele developed diabetes whereas NOD mice expressing the ß2Mb allele were protected. The mechanism of susceptibility and resistance conferred by ß2M has not been elucidated. In particular, it is not known how such a small change in ß2M could confer such a dramatic alteration in the immune response to islet tissue. It is not known which cell types impart ß2M mediated resistance and susceptibility to T1D. Utilizing the ß2M susceptible and ß2Mb resistant transgenic mice we are now dissecting out the role of different cell populations in the thymus, and in the periphery, which confer ß2M mediated protection and susceptibility.
Relevance to type 1 diabetics
Our understanding of the role of ß2M and MHC in directing the autoimmune killer T cell immune response is crucial to an understanding of how to regulate the disease in predisposed individuals. We have focused on the role of autoreactive B lymphocytes, and their role in expanding the population of killer CD8 T cells, since B cells are amenable to therapeutic intervention.
Publications
Kate L Graham, Balasubramanian Krishnamurthy, Stacey Fynch, Zia U Mollah, ROBYN SLATTERY, Pere Santamaria, Thomas W Kay, Helen E Thomas. Autoreactive cytotoxic T lymphocytes acquire higher expression of cytotoxic effector markers within the islets of NOD mice after priming in the pancreatic lymph nodes. Am J Pathol (2011) Vol 178:6, pp 2716-2725.
J.M. Forbes, J. Söderlund, F.Y.T Yap, M. Knip, S. Andrikopoulos, J. Ilonen, O. Simell, R. Veijola, K.C. Sourris, M.T. Coughlan, C. Forsblom, R. SLATTERY, S.T. Grey, M. Wessman, H. Yamamoto, A. Bierhaus, M.E. Cooper, P-H. Groop. Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes. Diabetologia (2011) Vol 54:5 pp1032-1042
Eveline Angstetra, Kate L Graham, Yuxing Zhao, Allison E Irvin, Lorraine Elkerbout, Pere Santamaria, ROBYN M SLATTERY, Thomas W Kay and Helen E Thomas. An indirect role for NK cells in a CD4+ T-cell-dependent mouse model of type I diabetes. Immunology and Cell Biology. (2011) March doi:10.1038/icb.2011.16 pp 1-5
Coughlan MT, Yap FY, Tong DC, Andrikopoulos S, Gasser A, Thallas-Bonke V, Webster DE, Miyazaki J, Kay TW, SLATTERY RM, Kaye DM, Drew BG, Kingwell BA, Fourlanos S, Groop PH, Harrison LC, Knip M, Forbes JM. Advanced glycation end products are direct modulators of β-cell function. Diabetes. (2011) Vol 60(10):2523-32.
Fletcher, JM., Jordan, MA., Snelgrove, SL., SLATTERY, RM., Dufour, FD., Kyparissoudis, K, Besra, GS., Godfrey, DI., Baxter, AG., Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4 J Immunol 2008
Ilmarinen, T., Kangas, H., Kytomaa T., Eskelin, P., Saharinen, J., Seeler, J., Tanhuanpaa, K., Chan, F.Y-L., SLATTERY, R.M., Alakurtti, K., Palvimo, J.J., Ulmanen, I. Functional Interaction of AIRE with PIAS1 in transcriptional Regulation Molecular Immunology 2008 45(7):1847-62.
de Jersey J, Snelgrove SL, Palmer SE, Teteris SA, Mullbacher A, Miller JF, Slattery RM. Beta cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2007;104(4):1295-300.
Serreze DV, Holl TM, Marron MP, Graser RT, Johnson EA, Choisy-Rossi C, Slattery RM, Lieberman SM, DiLorenzo TP. MHC class II molecules play a role in the selection of autoreactive class I-restricted CD8 T cells that are essential contributors to type 1 diabetes development in nonobese diabetic mice. J Immunol. 2004;172(2):871-9.
Hamilton-Williams EE, Palmer SE, Charlton B and Slattery RM. Beta cell MHC class I is a late requirement for diabetes. Proc Natl Acad Sci USA. 2003; 100: 6688-6693.
Silva D, Petrovsky N, Socha L, Slattery R, Gatenby P and Charlton B. Mechanisms of accelerated immune-mediated diabetes resulting from islet beta-cell expression of a FAS ligand transgene. J Immunol. 2003; 170: 4996-5002.
Hamilton-Williams EE, Serreze DV, Charlton B, Johnson EA, Marron MP, Mullbacher A and Slattery RM. Beta2-microglobulin identified as a diabetes susceptibility gene in NOD mice. Proc Natl Acad Sci USA. 2001; 98: 11533-11538.
Charlton B, DaZhang M and Slattery RM. B lymphocytes not required for progression from insulitis to diabetes in NOD mice. Immunol Cell Biol. 2001; 6: 597-601.
