T lymphocyte activation is tightly regulated to ensure effective elimination of invading pathogens as well as maintaining tolerance against self-tissues. On one hand, T cells are regulated by extracellular signals, especially the positive and negative costimulatory molecules on antigen-presenting cells, and on the other hand, also by delicate intracellular signal transducers and regulators. Recently, we found that T cells activated in the absence of both CD28 and ICOS costimulation became nonfunctional and nonresponsive, supporting a critical role of costimulation in T cell activation. These tolerant T cells not only were anergic with profound defects in TCR signal transduction but also completely lacked expression of effector-specific transcription factors. Interestingly, expression of Grail (gene related to anergy in lymphocytes), was only upregulated in T cells when both CD28 and ICOS signaling were absent. Grail is an E3 ubiquitin ligase whose expression was previously found to be associated with CD4 T cell anergy in vitro and in vivo. Blocking of negative costimulatory signals (B7S1, B7-H3 or PD-1) restored T cell function, associated with expression of effector-specific transcription factors and down-regulation of Grail expression. To determine the function of Grail in T cell activation and tolerance, we developed a Grail mutant mouse model. We found that Grail-deficient T cells were not dependent on CD28 and ICOS signaling in activation and effector differentiation in vitro. Our central hypothesis for the current study is that Grail molecule critically regulates T cell tolerance and function. We will first analyze the role of Grail in peripheral T cell tolerance. In addition, we will determine the mechanisms whereby Grail regulates T cell tolerance. Secondly, we will analyze the function of Grail in generation and function of natural and inducible Treg cells. Lastly, we will assess whether Grail deficiency will lead to susceptibility to autoimmune diseases and whether this is caused by defects in na?ve and/or Treg cells. These proposed studies will greatly advance our knowledge on Grail function in peripheral tolerance and autoimmune responses.

Public Health Relevance

T lymphocyte activation is tightly regulated to ensure effective elimination of invading pathogens as well as maintaining tolerance against self-tissues. On one hand, T cells are regulated by extracellular signals, especially the positive and negative costimulatory molecules on antigen-presenting cells, and on the other hand, also by delicate intracellular signal transducers and regulators. Our preliminary analysis of a Grail knockout mouse revealed its essential function in induction of T cell tolerance in vitro. In this project, we propose to continue our analysis on function of Grail in T cells in vitro and in vivo. These proposed studies will greatly advance our knowledge on Grail function in T cells and will provide a novel and unique insight into proper T cell regulation that governs self tolerance and immune function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083761-05
Application #
8468985
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$354,699
Indirect Cost
$124,375
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
Sahoo, Anupama; Alekseev, Andrei; Obertas, Lidiya et al. (2014) Grail controls Th2 cell development by targeting STAT6 for degradation. Nat Commun 5:4732
Liu, Xindong; Nurieva, Roza I; Dong, Chen (2013) Transcriptional regulation of follicular T-helper (Tfh) cells. Immunol Rev 252:139-45
Nurieva, Roza; Wang, Junmei; Sahoo, Anupama (2013) T-cell tolerance in cancer. Immunotherapy 5:513-31
Wang, Xiaohu; Zhang, Yibing; Yang, Xuexian O et al. (2012) Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity 36:23-31
Nurieva, Roza I; Podd, Andrew; Chen, Yuhong et al. (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 287:11234-9
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
Nurieva, Roza I; Chung, Yeonseok; Martinez, Gustavo J et al. (2009) Bcl6 mediates the development of T follicular helper cells. Science 325:1001-5
Zhang, Yongliang; Reynolds, Joseph M; Chang, Seon Hee et al. (2009) MKP-1 is necessary for T cell activation and function. J Biol Chem 284:30815-24
Nurieva, Roza I; Liu, Xikui; Dong, Chen (2009) Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev 229:88-100