: Self-reactive T cells are controlled by both central tolerance in the thymus and peripheral tolerance involving a variety of mechanisms. While genetic studies have established that peripheral tolerance is essential for preventing autoimmune diseases, no serious autoimmune disease has been attributed to defective central tolerance. Meanwhile, whereas it is well established that costimulatory molecules B7-1 and B7-2 play critical roles in the induction and effector function of T cells, their role in T cell development has not been well appreciated. We have recently demonstrated that perinatal blockade of B7-1 and B7-2 leads to an accumulation of autoreactive T cells in the thymus and prevents clonal deletion of autoreactive T cells, and that when transferred to immune-compromised hosts, these autoreactive T cells cause severe multiple organ inflammation with early lethality for young mice. These results reveal that costimulatory molecules B7-1 and B7-2 play an important role in T cell negative selection in the thymus and raise the intriguing possibility that defective central tolerance may contribute to the exacerbated autoimmune diseases in mice with germ-line mutations of CTLA4, CD28, or B7-2. Here we propose to systematically investigate the roles for CD28, CTLA4 and their shared ligands B7-1 and B7-2 in T cell clonal deletion and in the development of autoimmune diseases. Since these molecules are proposed to be involved in the development and/or function of CD25+CD4 T cells, we will also determine whether the autoreactive T cells that escape T cell clonal deletion can be effectively controlled by the regulatory T cells, and whether CTLA4 is critical for the regulatory function of the CD25+CD4 + T cells. ? ? Our proposed study will establish the function of B7-1 and B7-2 in negative selection of autoreactive T cells and evaluate the contribution of defective T cell clonal deletion and regulatory T cells to the development of autoimmune disease, a central tenet in contemporary immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051342-01A1
Application #
6574113
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$331,875
Indirect Cost
Name
Ohio State University
Department
Pathology
Type
Schools of Medicine
DUNS #
071650709
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zheng, Xincheng; Zhang, Huiming; Yin, Lijie et al. (2008) Modulation of NKT cell development by B7-CD28 interaction: an expanding horizon for costimulation. PLoS One 3:e2703
Zuo, Tao; Wang, Lizhong; Morrison, Carl et al. (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275-86
May Jr, Kenneth F; Chang, Xing; Zhang, Huiming et al. (2007) B7-deficient autoreactive T cells are highly susceptible to suppression by CD4(+)CD25(+) regulatory T cells. J Immunol 178:1542-52
Wang, Yin; Liu, Yan; Wu, Cindy et al. (2006) Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling. Cancer Cell 10:179-90
Chang, Xing; Chen, Li; Wen, Jing et al. (2006) Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection. Clin Immunol 121:274-85
Gao, Jian-Xin; Chang, Xing; Zheng, Xincheng et al. (2004) A new role for CD28 in the survival of autoreactive T cells in the periphery after chronic exposure to autoantigen. Int Immunol 16:1403-9
Zheng, Xincheng; Gao, Jian-Xin; Chang, Xing et al. (2004) B7-CD28 interaction promotes proliferation and survival but suppresses differentiation of CD4-CD8- T cells in the thymus. J Immunol 173:2253-61
Sarma, Supria; Bai, Xue-Feng; Liu, Jin-qing et al. (2003) On the role of unmutated antigens in tumor rejection in mice with unperturbed T-cell repertoires. Cancer Res 63:6051-5