The molecular mechanisms whereby the immune tolerance to self tissues is maintained are not well understood. T cell activation and tolerance is regulated by the innate immune system, importantly through co-stimulatory molecules. Activation of T cells in the absence of positive cositmulation (CD28 and ICOS) results in their tolerance and anergy, which is the main mechanism for peripheral tolerance of T cells in resting states. On the other hand, other costimulatory pathways, such as CTLA4 and PD-1 have been discovered to inhibit T cell activation. Thus, members of the B7 costimulator family, through their receptors in the CD28 family, play essential roles in determining T cell activation or self-tolerance. We have recently identified and characterized two new B7-like inhibitory molecules in mouse- B7-H3 and B7S1. Blocking antibodies against them exacerbated experimental allergic encephalomyelitis (EAE) disease in vivo. BTNL2 is a butyrophilin molecule we recently characterized that binds to activated T cell and inhibits their proliferation. Despite a large number of T cell inhibitors identified in the recent years, their specific physiological function in regulation of immune tolerance has not been well understood. In this application, we propose to compare the actions by B7-H3, B7S1 and BTNL2 in immune tolerance, specifically by analyzing their roles in peripheral tolerance and in pathogenesis of autoimmune disease models. First, we characterize the function of B7-H3 and B7S1 in peripheral tolerance mechanisms. Secondly, we will study the roles of B7- H3 and B7S1 in autoimmune disease models. Lastly, we will examine the expression and function of BTNL2. These studies will greatly improve our understanding of these novel costimulatory molecules in immune tolerance regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054912-05
Application #
7990008
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Lapham, Cheryl K
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$377,339
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Nurieva, Roza I; Zheng, Shuling; Jin, Wei et al. (2010) The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32:670-80
Liu, Xikui; Alexiou, Maria; Martin-Orozco, Natalia et al. (2009) Cutting edge: A critical role of B and T lymphocyte attenuator in peripheral T cell tolerance induction. J Immunol 182:4516-20
Nurieva, Roza; Yang, Xuexian O; Chung, Yeonseok et al. (2009) Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol 182:2565-8
Martin-Orozco, Natalia; Chung, Yeonseok; Chang, Seon Hee et al. (2009) Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39:216-24
Martin-Orozco, Natalia; Muranski, Pawel; Chung, Yeonseok et al. (2009) T Helper 17 Cells Promote Cytotoxic T Cell Activation in Tumor Immunity. Immunity :
Nurieva, Roza I; Chung, Yeonseok; Hwang, Daehee et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138-49
Martin-Orozco, Natalia; Dong, Chen (2007) Inhibitory costimulation and anti-tumor immunity. Semin Cancer Biol 17:288-98