Regulatory CD4 T lymphocytes (Treg) are critical for the maintenance of self-tolerance. This is a Program Project grant application to identify the factors that will allow for the most efficient generation and/or stabilization and In vivo function of Treg. Several types of Treg have been identified, the best characterized ones, including subsets that express the transcription factor Foxp3, and ones that produce IL-10, will be studied in the proposed experiments. The principal investigators have laboratories In proximity and they interact extensively. The members of this group have complementary areas of expertise ranging from gene transcription studies to the set up of clinical trials. They work in relevant animal models of infection and immune mediated diseases such as type I diabetes, colitis and asthma. In Project 1, led by Dr. Liu, we will investigate how an E3 ubiquitin ligase, Cbl-b, stimulates Foxp3 induction, via a pathway that leads to increased activity of the transcription factor Foxo3a. Project 2, from Dr. Kronenberg, will explore the genetic and functional changes that occur when Treg lose Foxp3 expression and suppressive function, and will analyze the function of the intestinal myeloid cells that provide the critical IL-10 required for Treg maintenance in mice with colitis. In Project 3, led by Dr. von Herrath and his group, we will explore how the function of different types of Treg are altered by viral infections, and we will determine how the innate responses by antigen presenting cells to viruses mediate effects on Treg. In Project 4 led by Dr. Croft, we will examine the lectins Galectins-3 and -9, which we have shown are novel ligands for the TNF family receptor 4-1 BB. We will determine the mechanism whereby this interaction influences the induction of Foxp3 expression. The proposed research will be supported by an Administrative Core and a Biostatistics/Bioinformatics core that also will assist with the multi-parameter analysis of cytokines. Methods employed will include cutting edge genetic technologies as well as in vivo models of important immune diseases. The findings from this research will help in understanding the means for creating effective Treg-based Immune therapies for the treatment of autoimmune and inflammatory diseases.

Public Health Relevance

The immune system prevents infections, but can also create autoimmune or inflammatory diseases such as type I diabetes and asthma. Regulatory T cells prevent such over exuberant immune responses, and it may be possible to use these cells as a novel therapy. We will use cutting edge methods to provide a better understanding of the ways to improve the ability of regulatory T cells to prevent autoimmune disease. PROJECT 1: Title: Transcriptional Regulation of Foxp3 Expression by Protein Ubiquitination Project Leader: Liu, Y. PROJECT 1 DESCRIPTION (provided by applicant): Our long-term goal is to study the regulation of immune responses under normal and diseased conditions, particularly the invovlement of protein ubiquitination pathway in lymphocyte development, activation, and tolerance inductiion. Cbl-b is composed of an N-terminal tyrosine kinase binding domain, a RING finger, and C-terminal proline-rich sequences. Genetic studies using Cbl-b deficient mice have shown that Cbl-b is critical in T cell activation, and loss of Cbl-b results in increased autoimmunity. Cbl-b functions as RING-type E3 ubiquitin ligase to promote ubiquitin conjugation to critical signaling molelcules and affects their biological functions. More importantly, we showed that Cbl-b is upregulated during T cell anergy induction and controls the tolerigenic process, thus linking protein ubiquitination pathway to the T cell tolerance. We have recently obtained some unexpected and novel observations. Particularly, we found that Cbl-b is involved in the regulation of Foxp3 expression in inducible regulatory T cells (iTregs) via modulating a novel signaling pathway directly acting at the transcriptional regulation of Foxp3 gene. The new findings form a strong basis for us to hypothesize that Cbl-b plays an essential role in controlling immune responses via promoting protein ubiquitination. In this proposal, we wll plan: 1) to investigate the molecular mechanisms by which Cbl-b E3 ubiquitn ligase regulates Foxp3 gene transcription via modulating Foxo3a-directed gene transcription and to perform genome-wide gene profiling of Tregs to understand the molecular regulation of epigenetic control in Tregs;2) to examine the in vivo function of iTregs in mouse models of autoimmunity and airway inflammation. These studies will significantly advance our understanding of the molecular mechanisms governing Foxp3 gene transcription and iTreg-mediated immune regulation. Such knowledge will eventually facilitate the design of novel therapeutic approaches for cancer, autoimmune and allergic diseases.

Public Health Relevance

The immune system has evolved to mount robust responses against invading pathogens, but at the same time is tolerant to self-tissues or self-antigens. The mechanisms governing immune tolerance are not clear. This proposal will study the mechanisms by which the immune responses are properly controlled. Such knowledge will eventually facilitate the design of novel therapeutic approaches for immunological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI089624-04
Application #
8495221
Study Section
Special Emphasis Panel (ZAI1-SV-I (M1))
Program Officer
Lapham, Cheryl K
Project Start
2010-07-16
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$1,910,004
Indirect Cost
$898,885
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Park, Yoon; Jin, Hyung-Seung; Lopez, Justine et al. (2016) SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat Immunol 17:286-96
Lee, Jee H; Elly, Chris; Park, Yoon et al. (2015) E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1α to Maintain Regulatory T Cell Stability and Suppressive Capacity. Immunity 42:1062-74
Aki, Daisuke; Zhang, Wen; Liu, Yun-Cai (2015) The E3 ligase Itch in immune regulation and beyond. Immunol Rev 266:6-26
Eun, So-Young; Lee, Seung-Woo; Xu, Yanfei et al. (2015) 4-1BB ligand signaling to T cells limits T cell activation. J Immunol 194:134-41
Krause, Petra; Morris, Venetia; Greenbaum, Jason A et al. (2015) IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis. Nat Commun 6:7055
Kong, Kok-Fai; Fu, Guo; Zhang, Yaoyang et al. (2014) Protein kinase C-η controls CTLA-4-mediated regulatory T cell function. Nat Immunol 15:465-72
Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90
Madireddi, Shravan; Eun, So-Young; Lee, Seung-Woo et al. (2014) Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. J Exp Med 211:1433-48
Duan, Wei; Croft, Michael (2014) Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann Am Thorac Soc 11 Suppl 5:S306-13
Baca Jones, Carmen; Pagni, Philippe P; Fousteri, Georgia et al. (2014) Regulatory T cells control diabetes without compromising acute anti-viral defense. Clin Immunol 153:298-307

Showing the most recent 10 out of 37 publications