The mechanism that lead to tolerization of autoreactive T cells to restricted peripheral antigens, such as islets antigens, have not been well defined. In addition autoreactive T cells that escape from negative selection and cause autoimmune diabetes have also not been well elucidated. Autoimmune regular (AIRE) is a newly discovered transcription factor regulating peripherally restricted antigens in thymic medulla epithelial cells (mTECs), that might control the deletion of the autoreactive T cells. Lack of AIRE in patients, or in mice leads to increased incidences of endocrine organ-specific autoimmunity. On the other hand, the lack of lymphotoxin (LT) causes wider lymphocyte infiltration into multiple organs. Our preliminary data showed that the LT beta receptor signaling pathway, possibly through NF-kB subunits, was necessary for the expression of self antigens in AIRE-dependent and independent pathway. We hypothesize that LT controls the expression of autoantigens in both an AIRE-dependent and -independent pathways leading to negative selection of autoreactive T cells. Furthermore, coordination of T cells escaping negative selection leads to persistent local inflammation, which is required for tissue-specific autoimmune destruction. 1) Using antibodies and soluble receptors to stimulating or inhibiting the LTBR pathway as well as using LTBR and AIRE KO mice, we will define AIRE-dependent and independent pathways involved in negative selection. We will define which NF-kB pathways, namely p52/RelB, p50/RelB, p52/RelA, or p50/RelA, is essential for LT-mediated AIRE induction of insulin; 2) We will address the role of local inflammation, increased apoptosis, and costimulation, in recruiting and activating these escaped autoreactive T cells inside islets causing autoimmune diabetes. The goal of this project is to define how autoreactive T cells are controlled by the stromal cells within the thymic and peripheral tissues and how cross-talk between autoreactive T cells against peripheral antigens and stromal cells dictates the development of autoimmune diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058897-08
Application #
7393677
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2001-05-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
8
Fiscal Year
2008
Total Cost
$333,010
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Wang, Yugang; Koroleva, Ekaterina P; Kruglov, Andrei A et al. (2010) Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32:403-13
Zhu, Mingzhao; Brown, Nicholas K; Fu, Yang-Xin (2010) Direct and indirect roles of the LTbetaR pathway in central tolerance induction. Trends Immunol 31:325-31
Tumanov, Alexei V; Koroleva, Ekaterina P; Christiansen, Peter A et al. (2009) T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 136:694-704.e4
Sun, Yonglian; Brown, Nicholas K; Ruddy, Matthew J et al. (2009) B and T lymphocyte attenuator tempers early infection immunity. J Immunol 183:1946-51
Yu, Ping; Fu, Yang-Xin (2008) Targeting tumors with LIGHT to generate metastasis-clearing immunity. Cytokine Growth Factor Rev 19:285-94
Schwarz, Brad T; Wang, Fengjun; Shen, Le et al. (2007) LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology 132:2383-94
Kim, Kwang Dong; Zhao, Jie; Auh, Sogyong et al. (2007) Adaptive immune cells temper initial innate responses. Nat Med 13:1248-52
Yu, Ping; Lee, Youjin; Wang, Yang et al. (2007) Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases. J Immunol 179:1960-8
Zhu, Mingzhao; Chin, Robert K; Tumanov, Alexei V et al. (2007) Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J Immunol 179:8069-75
Zhu, Mingzhao; Chin, Robert K; Christiansen, Peter A et al. (2006) NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J Clin Invest 116:2964-71

Showing the most recent 10 out of 32 publications