CD4+ Foxp3+ regulatory T (Treg) cells are important for maintaining immune tolerance, preventing autoimmune diseases, and fine-tuning of immune responses against invading pathogens. Although multiple transcription factors and signaling pathways that positively regulate natural Treg (nTreg) differentiation have been identified, little is known about the negative regulatory mechanism involved in the process. Our recent studies showed that the SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated PIAS1) restricts the differentiation of nTreg cells by maintaining a repressive chromatin state of the Foxp3 promoter. Pias1 deletion caused promoter demethylation, reduced H3K9 methylation, and enhanced promoter accessibility. Consistently, Pias1-/- mice displayed an increased nTreg population and were resistant to the development of experimental autoimmune encephalomyelitis. Our studies have identified an epigenetic mechanism that negatively regulates the differentiation of Treg cells. This application proposes experiments to directly address the deficiencies in our knowledge on Treg cells by studying the molecular mechanism and the biological significance of the newly identified PIAS1 epigenetic pathway in the differentiation and plasticity of Treg cells. Specifically, Aim 1 and Aim 2 will characterize the newly identified PIAS1 epigenetic pathway by testing novel aspects of the molecular mechanisms, including the exploration of previously unrecognized role of protein sumoylation in the epigenetic control of Treg cells and the analysis of specificity of the PIAS1 epigenetic pathway in Treg differentiation.
Aim 3 will study the plasticity of Treg cells through an epigenetic approach. We will examine the reprogramming of Treg cells using novel animal models in which the epigenetic status of Treg cells is altered through Pias1 disruption. The successful completion of these studies will uncover novel molecular mechanisms involved in the negative regulation of Treg cells and will advance our ability to design effective therapeutic strategy for the treatment of autoimmune diseases.

Public Health Relevance

A subtype of T cells named CD4+ Foxp3+ regulatory T (Treg) cells play important roles in control immune tolerance. The abnormal regulation of Treg cells is associated with the development of immune disorders such as autoimmune diseases. Our goal is to characterize a newly identified pathway that negatively regulates Treg cells.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI063286-06A1
Application #
8631959
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Liu, Bin; Yee, Kathleen M; Tahk, Samuel et al. (2014) PIAS1 SUMO ligase regulates the self-renewal and differentiation of hematopoietic stem cells. EMBO J 33:101-13
Liu, Bin; Tahk, Samuel; Yee, Kathleen M et al. (2014) PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing. PLoS One 9:e89464
Liu, Bin; Tahk, Samuel; Yee, Kathleen M et al. (2010) The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330:521-5
Liu, Bin; Shuai, Ke (2008) Targeting the PIAS1 SUMO ligase pathway to control inflammation. Trends Pharmacol Sci 29:505-9
Liu, Bin; Shuai, Ke (2008) Regulation of the sumoylation system in gene expression. Curr Opin Cell Biol 20:288-93