T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative during clinical organ transplantation in humans. Anergy involves the functional inactivation of inappropriate T cell responses, and is thought to be the result of active silencing of effector genes such as interleukin-2 (IL-2). Our progress during the first funding period of this grant established that cell cycle progression is necessary for activated T cells to escape anergy during a productive immune response, and defined a previously unappreciated role for cyclin-dependent kinases (CDK) and their genetically-encoded inhibitory proteins in the decision between T cell immunity and tolerance. The activity of these kinases opposed the induction of T cell clonal anergy in vitro, and genetic dysregulation of CDK activity during organ transplantation interfered with tolerance induced by costimulatory blockade.

Public Health Relevance

The goal of this proposal is to explore the molecular mechanisms by which cyclin-dependent kinases regulate T lymphocyte function, and to evaluate the potential of these molecules as therapeutic targets in pre-clinical models of organ transplantation. A deeper understanding of the molecular events underlying T cell tolerance could lead to new approaches to induce tolerance in the setting of autoimmunity and transplantation, and therefore the research proposed in the is application is consistent with and highly relevant to the NIH/HHS goal of improving human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054643-10
Application #
8264559
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2002-07-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$403,066
Indirect Cost
$158,041
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Morawski, Peter A; Mehra, Parul; Chen, Chunxia et al. (2013) Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J Biol Chem 288:24494-502
Wells, Andrew D (2007) Cyclin-dependent kinases: molecular switches controlling anergy and potential therapeutic targets for tolerance. Semin Immunol 19:173-9
Chen, Chunxia; Wells, Andrew D (2007) Comparative analysis of E2F family member oncogenic activity. PLoS One 2:e912
Rowell, Emily A; Wang, Liqing; Hancock, Wayne W et al. (2006) The cyclin-dependent kinase inhibitor p27kip1 is required for transplantation tolerance induced by costimulatory blockade. J Immunol 177:5169-76
Rowell, Emily A; Wells, Andrew D (2006) The role of cyclin-dependent kinases in T-cell development, proliferation, and function. Crit Rev Immunol 26:189-212
Rowell, Emily A; Walsh, Matthew C; Wells, Andrew D (2005) Opposing roles for the cyclin-dependent kinase inhibitor p27kip1 in the control of CD4+ T cell proliferation and effector function. J Immunol 174:3359-68
Thomas, Rajan M; Gao, Ling; Wells, Andrew D (2005) Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. J Immunol 174:4639-46
Wells, Andrew D; Liu, Qing-Hua; Hondowicz, Brian et al. (2003) Regulation of T cell activation and tolerance by phospholipase C gamma-1-dependent integrin avidity modulation. J Immunol 170:4127-33