Naturally occurring as well as adaptively developed Foxp3+CD4+ regulatory T cells (Treg) are central to the maintenance of immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. Treg specifically express the transcription factor Foxp3, which mediates the coordinate activation of genes such as CTLA-4 and GITR along with silencing of cytokines such as interleukin-2, IL-17 and interferon-?, that are normally expressed by effector T cells (Teff). The functional boundary between Treg and the Teff they are meant to suppress is not absolute. In fact, the flexibility between Treg and Teff may be an important component to both physiologic and pathophysiologic immune responses. Understanding this functional interchange requires an understanding of how immune effector genes are normally silenced in Treg. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression has not been elucidated. Recently, we identified Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in Treg. Eos interacts directly with Foxp3 and is necessary for gene silencing without affecting expression of Foxp3 activated genes. We further demonstrated that Eos and its corepressor C-terminal binding protein 1 (CtBP1) are necessary for histone modifications and ultimately promoter methylation involved in selective gene silencing in Treg. Knockdown of Eos in Treg abrogates their ability to suppress immune responses in vitro and in vivo. We hypothesize that Eos-CtBP-1 gene silencing is a highly regulated process in Treg that impacts on their function as suppressors vs. effectors of immunity. In the current proposal, we will further explore metabolic and microRNA dependent mechanisms of regulation of Eos-CtBP1 gene silencing in Treg as well as the in vivo consequences of ablation of this pathway for Treg development, homeostasis and modulation of adaptive immune responses. Specifically, we will 1) Elucidate the role of metabolic stimuli that affect NADH/NAD balance in Eos mediated gene silencing via the CtBP1 complex, 2) Study the regulation of Eos expression in Treg cells by microRNAs and 3) Study the consequences of Eos deletion to Treg cell homeostasis, differentiation and adaptive Treg cell development.

Public Health Relevance

Foxp3 is a critical transcription factor that mediates both gene activation and gene repression in regulatory T cells. We have discovered a specific molecule, term Eos, that is selectively responsible for gene silencing in regulatory T cell. This proposal explore mechanism of Eos dependent Gene silencing and test the hypothesis that regulation of Eos is an important mechanism to control the regulatory T cell/ effector T cell balance in immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI089830-01
Application #
7947180
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$410,000
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lu, Ling; Barbi, Joseph; Pan, Fan (2017) The regulation of immune tolerance by FOXP3. Nat Rev Immunol 17:703-717
Park, Benjamin V; Freeman, Zachary T; Ghasemzadeh, Ali et al. (2016) TGF?1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer. Cancer Discov 6:1366-1381
Yang, Huang-Yu; Barbi, Joseph; Wu, Chao-Yi et al. (2016) MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor. Immunity 45:83-93
Tao, Jin-Hui; Barbi, Joseph; Pan, Fan (2015) Hypoxia-inducible factors in T lymphocyte differentiation and function. A Review in the Theme: Cellular Responses to Hypoxia. Am J Physiol Cell Physiol 309:C580-9
Barbi, Joseph; Pardoll, Drew M; Pan, Fan (2015) Ubiquitin-dependent regulation of Foxp3 and Treg function. Immunol Rev 266:27-45
Park, Benjamin V; Pan, Fan (2015) Metabolic regulation of T cell differentiation and function. Mol Immunol 68:497-506
Park, Benjamin V; Pan, Fan (2015) The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases. Cell Mol Immunol 12:533-42
Pan, Fan; Barbi, Joseph (2014) Ubiquitous points of control over regulatory T cells. J Mol Med (Berl) 92:555-69
Barbi, Joseph; Pardoll, Drew; Pan, Fan (2014) Treg functional stability and its responsiveness to the microenvironment. Immunol Rev 259:115-39
Sharma, Madhav D; Huang, Lei; Choi, Jeong-Hyeon et al. (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38:998-1012

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