The Use of Idd Congenic Mice to Identify Checkpoints of Peripheral Tolerance to Islet Antigen EMMA E. HAMILTON-WILLIAMS, a XAVIER MARTINEZ, a MICHAEL LYMAN, a KARA HUNTER, b LINDA S. WICKER, b AND LINDA A. SHERMAN a a Department of Immunology, The Scripps Research Institute, La Jolla, California, USA b JDRF/WT Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0XY United Kingdom ABSTRACT: Type 1 diabetes (T1D) occurs because of lack of T cell toler- ance to islet antigens. We hypothesized that critical genetic susceptibility loci that control progression to T1D, designated as insulin-dependent dia- betes (Idd) loci, would be responsible for preventing CD8 T cell tolerance. To test this hypothesis, we have used two different congenic non-obese diabetic (NOD) mice that are highly protected from the occurrence of T1D because they express protective alleles at Idd3 and Idd5.1, 5.2, 5.3 (Idd3/5 mice), or at Idd9.1, 9.2, and 9.3 (Idd9 mice). By examining the CD8 T response to two different islet-expressed antigens, we have deter- mined that CD8 T tolerance is restored in both strains of mice. However, tolerance occurs at different checkpoints in each strain. In Idd3/5 mice, islet-antigen-specific CD8 T cells are eliminated in the pancreatic lymph nodes, where they are first activated by cross-presented islet antigens. In contrast, in Idd9 mice autoreactive CD8 T cells accumulate at this site and are not tolerized until after they enter the pancreas. We are currently identifying the cell types and mechanisms that are critical for tolerance induction at each checkpoint. KEYWORDS: type 1 diabetes; CD8 T lymphocytes; autoimmunity; NOD mouse INTRODUCTION Type 1 diabetes (T1D) is a serious chronic disease affecting an increasing number of individuals each year. This disease is caused by a combination of Address for correspondence: Dr. Linda A. Sherman. Department of Immunology, The Scripps Re- search Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Voice: 1-858-784-8446; fax: 1-858-784-8298. lsherman@scripps.edu Ann. N.Y. Acad. Sci. 1103: 118–127 (2007). C  2007 New York Academy of Sciences. doi: 10.1196/annals.1394.003 118