Regulatory T cell (Treg) plays a critical role in maintaining immune system homeostasis and preventing autoimmunity and immunopathology. Compromised Treg function is linked to multiple autoimmune diseases including type 1 diabetes and multiple sclerosis. On the flip side, enrichment of Treg cells within tumors is thought to be a barrier to effective anti-tumor immune response. The development and maintenance of Treg cell lineage are dependent on transcription factor Foxp3, as loss of function mutations lead to severe lymphoproliferative disease in mice and humans. Thus, understanding the mechanisms that govern Foxp3 induction and stability may lead to the development of novel therapies for autoimmune disease and cancer. Previously, Dr. Zheng and colleagues identified three evolutionarily conserved cis-regulatory elements at the Foxp3 locus, which play unique roles in Treg differentiation or maintenance. To expand this line of research, Dr. Zheng?s group will use a CRISPR/Cas9 based approach named CREST-seq (cis-regulatory element scan by tiling-deletion and sequencing) to perform unbiased screen and functional assessment for distal cis-elements near the Foxp3 locus. A preliminary study showed there are potentially up to 50 cis-regulatory elements involved in the control of Foxp3 expression. In-depth characterization of these new cis-elements will advance the understandings on the regulatory circuitry of Foxp3 expression. Numerous studies generated annotations on millions of candidate regulatory elements for thousands of genes in Tregs, but understanding is incomplete on how these elements control their target genes that are kilo-bases or even mega-bases away. Preliminary studies on genome-wide chromosome looping in Tregs generated a collection of distal DNA loops that can potentially regulate Treg signature genes. Furthermore, these data suggest a novel role for Foxp3 in facilitating distal DNA looping. To better understand how cis-regulatory circuitry control Treg differentiation and function, Dr. Zheng?s group will identify and characterize the cis-elements that control Foxp3 expression by a tiling deletion based genetic screen (Aim 1) and explore how distal enhancers regulate gene expression in regulatory T cell through chromosome looping (Aim 2). Furthermore, they will investigate if Foxp3 facilitates chromosome looping to establish and maintain the Treg lineage. Since Treg cell is directly related to autoimmune diseases and cancer, Dr. Zheng?s study will provide insight into the molecular mechanisms of Treg development and function and offer new opportunities to manipulate Tregs for therapeutic purposes.

Public Health Relevance

Regulatory T cells (Tregs) are a subset of T lymphocytes that function as suppressor of the immune system and play a critical role in preventing autoimmune diseases. The goal of this project is to investigate the regulatory network that defines Treg cell differentiation and function. The outcome of this project can potentially lead to the development of novel therapies for autoimmune disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI107027-06
Application #
9670690
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ramachandra, Lakshmi
Project Start
2014-01-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Cao, Qi; Zhao, Xuan; Bai, Jingwen et al. (2017) Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci U S A 114:12548-12553
Zheng, Ye (2017) A Rogue Foxp3 Mutant Undermines Treg Cell Function. Immunity 47:211-214
Klann, Jane E; Remedios, Kelly A; Kim, Stephanie H et al. (2017) Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool. J Immunol 198:4639-4651
He, Nanhai; Fan, Weiwei; Henriquez, Brian et al. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114:12542-12547
Wang, Jianrong; He, Nanhai; Zhang, Na et al. (2017) NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection. Nat Commun 8:959
Chinen, Takatoshi; Kannan, Arun K; Levine, Andrew G et al. (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol 17:1322-1333
Liu, Wen-Hsien; Kang, Seung Goo; Huang, Zhe et al. (2016) A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells. J Exp Med 213:1901-19
Hernandez, Jeniffer B; Chang, Christina; LeBlanc, Mathias et al. (2015) The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nat Commun 6:7216
Bapat, Sagar P; Myoung Suh, Jae; Fang, Sungsoon et al. (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528:137-41
Li, Xudong; Zheng, Ye (2015) Regulatory T cell identity: formation and maintenance. Trends Immunol 36:344-53

Showing the most recent 10 out of 13 publications