Type 1 diabetes (T1D) is an autoimmune disease characterized by the highly specific destruction of the pancreatic pcells. Numerous studies have demonstrated that the primary mediators of p cell destruction are CD4+ and CD8+ T cells. Aberrant thymic selection and failing peripheral tolerance are believed to contribute to the development of pathogenic T cells, however, the precise mechanisms that over-ride self-tolerance still require elucidation. We have been studying the role of professional antigen presenting cells (ARC) such as macrophages (Me) and dendritic cells (DC) in the initiation and establishment of T1D. Recently, we have found that the progression of p cell autoimmunity is profoundly altered in nonobese diabetic (NOD) mice deficient in MerTK expression (NOD.mertk ). MerTK is a receptor tyrosine kinase expressed by Me and DC among other cell types. NOD.mertkKD mice remain diabetes-free and preliminary data suggest that protection correlates with enhanced negative selection in the thymus. In marked contrast, p cell autoimmunity is exacerbated in NOD.mertk mice transgenic for the pcell-specific BDC2.5 clonotypic T cell receptor. Here, "enhanced" T1D is associated with events ongoing in the periphery. Notably, MerTK has been reported to serve various functions including apoptotic body uptake, and maintaining homeostasis of ARC activation. Strikingly, the gene encoding MerTK is located in the NOD insulin-dependent diabetes (Idd) 13 (Idd13) susceptibility locus and is conserved in the human IDDM13 locus. Based on our findings with NOD.mertk mice, MerTK may in fact have a key role in contributing to T1D. Accordingly, the current application will focus on determining the role(s) of MerTK in regulating the development and expansion of pcell-specific T cells in the context of thymic selection and peripheral tolerance. In this way, the cellular and molecular contribution of MerTK in regulating ARC activation and effector function, and how these events shape p cell-specific T cell reactivity will be ascertained.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066075-03
Application #
7350169
Study Section
Special Emphasis Panel (ZRG1-IMM-B (02))
Program Officer
Esch, Thomas R
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$346,094
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Cowherd, Rachael B; Cowerd, Rachael B; Asmar, Melissa M et al. (2010) Adiponectin lowers glucose production by increasing SOGA. Am J Pathol 177:1936-45
Yi, Zuoan; Li, Li; Matsushima, Glenn K et al. (2009) A novel role for c-Src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells. Blood 114:3191-8
Wallet, Mark A; Flores, Rafael R; Wang, Yaming et al. (2009) MerTK regulates thymic selection of autoreactive T cells. Proc Natl Acad Sci U S A 106:4810-5
Wallet, Mark A; Sen, Pradip; Flores, Rafael R et al. (2008) MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med 205:219-32
Sen, Pradip; Wallet, Mark A; Yi, Zuoan et al. (2007) Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells. Blood 109:653-60