The proliferation of a few, antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, costimulatory and growth factor receptors, and is controlled by the cyclin-dependent kinase (CDK) cascade. Our work during the last two funding periods has focused on the role of cyclin-dependent kinases in T cell differentiation, anergy and tolerance. Our work established critical roles for CDK2 and its inhibitor p27kip1 in controlling the balance between immunity and tolerance. We showed that mice with a germline deletion of CDK2 accept cardiac allografts under conditions that lead to rejection in wild-type recipients, while mice lacking p27kip1 are highly resistant to tolerance induced by costimulatory blockade. Surprisingly, these factors do not operate through regulation of T cell cycle progression. Instead, we found that CDK2 activity promotes T helper differentiation, and that CDK2-deficient Treg exhibit a gain of suppressive activity. In this renewal application, we will explore this exciting new role for the CDK2 pathway in the control of regulatory T cell function, focused mainly by our findings that Foxp3 is phosphorylated and targeted for degradation by CDK2, and that dysregulated CDK2 activity opposes the induction and stability of Foxp3+ Treg. The proposed work will forward our basic understanding of how Foxp3 and regulatory T cell function is regulated, and will also have important therapeutic implications. Small molecule CDK antagonists are currently in phase I clinical trials, and based on our findings, could potentially be used to promote regulatory T cell function and tolerance in autoimmune and organ transplant patients.

Public Health Relevance

Autoimmunity and organ transplant rejection result from a break down of the 'checks and balances' that normally limit activation of the cells of the immune system, and have an economic impact of over 100 billion dollars per year. We have identified an unexpected and exciting link between a basic biochemical pathway involved in regulating cell growth, called the cyclin-dependent kinase cascade, and the function of a factor called Foxp3 that is required to guard against autoimmunity and chronic inflammation. Cyclin-dependent kinase inhibitory drugs are currently in phase I clinical trials, so we think these drugs could potentially be re-purposed to promote Foxp3 function, inhibit inflammation, and reverse immunopathologic disease in autoimmune and organ transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054643-12
Application #
9173017
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Ramachandra, Lakshmi
Project Start
2002-07-15
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
O'Brien, Shaun; Thomas, Rajan M; Wertheim, Gerald B et al. (2014) Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production. J Immunol 192:5118-29
Wells, Andrew D; Morawski, Peter A (2014) New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation. Nat Rev Immunol 14:261-70
Wu, Zhengli; Chen, Xiaochun; Liu, Fang et al. (2014) Calpain-1 contributes to IgE-mediated mast cell activation. J Immunol 192:5130-9
Rowell, Emily A; Wang, Liqing; Chunder, Neelanjana et al. (2014) Regulation of T cell differentiation and alloimmunity by the cyclin-dependent kinase inhibitor p18ink4c. PLoS One 9:e91587
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
Thomas, Rajan M; Sai, Hong; Wells, Andrew D (2012) Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus. J Biol Chem 287:25049-59
Chunder, Neelanjana; Wang, Liqing; Chen, Chunxia et al. (2012) Cyclin-dependent kinase 2 controls peripheral immune tolerance. J Immunol 189:5659-66
Wells, Andrew D (2010) Mutiny on the Boun-T: controlling dangerous T cells through anergy. Discov Med 9:16-9
Wells, Andrew D (2009) New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182:7331-41
Wells, Andrew D (2007) Cyclin-dependent kinases: molecular switches controlling anergy and potential therapeutic targets for tolerance. Semin Immunol 19:173-9

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