Autoimmune diabetes is a regulated disease. There are distinct lags before the initiation of insulitis (checkpoint-I) and between the development of insulitis and diabetes (checkpoint-2). These pauses are evident in the NOD mouse model of diabetes, but are most easily studied in the BDC2.5 T cell receptor transgenic model. This proposal focuses on checkpoint-1. Naive diabetogenic T cells do not first encounter their pancreatic-islet B-cell specific antigen in the islets, themselves, but rather in the lymph nodes directly draining them. A likely scenario is that dendritic cells located in the islets somehow pick up beta-cell proteins; the now-activated cells migrate to the pancreatic lymph nodes, at the same time processing the internalized proteins to peptides, displaying the peptides in major histocompatibility complex class II molecules at the cell surface, and upregulating costimulatory molecules; the now-mature dendritic cells stimulate naive diabetogenic T cells circulating through the nodes, prompting them to migrate through the tissues; finally, the roving T cells re-encounter their cognate antigen on dendritic cells located in the islets, leading to their re-stimulation and retention. Checkpoint-1 reflects an impediment in this scenario: for some reason, in very young mice, B-cell-specific antigens are not made available to murine T cells circulating through the pancreatic lymph node. This application aims to identify the impediment in very young mice, and to determine how it is eventually lifted. More specifically, it describes experiments that will: i) determine whether a wave of islet-beta-cell death known to occur in juvenile rodents is accompanied by dendritic cell engulfment of beta-cell proteins and their activation; ii) assess the role of cell death-signalling molecules, most particularly caspase-12, in checkpoint-1; and iii) establish whether or not changes in dendritic cell subsets in the first weeks after birth play any role in checkpoint-1. These studies should illuminate the events surrounding the triggering of autoimmune diabetes, providing a framework for elucidating the differences between susceptible and resistant individuals, and perhaps providing new leads for interventional drug targets.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
Kriegel, Martin A; Sefik, Esen; Hill, Jonathan A et al. (2011) Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U S A 108:11548-53
Mathis, Diane; Benoist, Christophe (2010) Levees of immunological tolerance. Nat Immunol 11:3-6
Suwanai, Hirotsugu; Wilcox, Martha Angela; Mathis, Diane et al. (2010) A defective Il15 allele underlies the deficiency in natural killer cell activity in nonobese diabetic mice. Proc Natl Acad Sci U S A 107:9305-10
Feuerer, Markus; Shen, Yuelei; Littman, Dan R et al. (2009) How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity 31:654-64
Mathis, Diane; Benoist, Christophe (2007) A decade of AIRE. Nat Rev Immunol 7:645-50
Hyatt, Gordon; Melamed, Rachel; Park, Richard et al. (2006) Gene expression microarrays: glimpses of the immunological genome. Nat Immunol 7:686-91
Turley, Shannon J; Lee, Je-Wook; Dutton-Swain, Nick et al. (2005) Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc Natl Acad Sci U S A 102:17729-33
Vence, Luis; Benoist, Christophe; Mathis, Diane (2004) Fas deficiency prevents type 1 diabetes by inducing hyporesponsiveness in islet beta-cell-reactive T-cells. Diabetes 53:2797-803
Denis, Maria C; Mahmood, Umar; Benoist, Christophe et al. (2004) Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc Natl Acad Sci U S A 101:12634-9
Turley, Shannon; Poirot, Laurent; Hattori, Masakazu et al. (2003) Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 198:1527-37

Showing the most recent 10 out of 12 publications