Induction and maintenance of regulatory T cells

Summary

Principal Investigator: Mitchell Kronenberg
Abstract: DESCRIPTION (provided by applicant): 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. 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. 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.
Funding Period: 2010-07-16 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. ncbi The TNF family in T cell differentiation and function--unanswered questions and future directions
    Michael Croft
    Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, United States Electronic address
    Semin Immunol 26:183-90. 2014
  2. pmc TSC1 regulates the balance between effector and regulatory T cells
    Yoon Park
    J Clin Invest 123:5165-78. 2013
  3. pmc Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1
    Tobias Boettler
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
    J Immunol 191:5026-35. 2013
  4. pmc A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes
    Gisen Kim
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    J Immunol 190:1510-8. 2013
  5. pmc Clinical targeting of the TNF and TNFR superfamilies
    Michael Croft
    Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
    Nat Rev Drug Discov 12:147-68. 2013
  6. pmc The microbiology of human hygiene and its impact on type 1 diabetes
    Nora M Chapman
    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
    Islets 4:253-61. 2012
  7. pmc OX40 facilitates control of a persistent virus infection
    Tobias Boettler
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America
    PLoS Pathog 8:e1002913. 2012
  8. pmc Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice
    Ekaterina K Koltsova
    Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Circ Res 111:1274-85. 2012
  9. pmc Novel transmembrane protein 126A (TMEM126A) couples with CD137L reverse signals in myeloid cells
    Jun Sang Bae
    Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130 701, Republic of Korea
    Cell Signal 24:2227-36. 2012
  10. pmc TNF superfamily in inflammatory disease: translating basic insights
    Michael Croft
    La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, 9420 Athena Circle, La Jolla, CA 92037, USA
    Trends Immunol 33:144-52. 2012

Detail Information

Publications13

  1. ncbi The TNF family in T cell differentiation and function--unanswered questions and future directions
    Michael Croft
    Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, United States Electronic address
    Semin Immunol 26:183-90. 2014
    ..Expanding our knowledge of how the TNF/TNFR family control T cells will undoubtedly help fulfill the promise of these molecules for providing efficacious clinical therapy of immune system disease. ..
  2. pmc TSC1 regulates the balance between effector and regulatory T cells
    Yoon Park
    J Clin Invest 123:5165-78. 2013
    ..Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination. ..
  3. pmc Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1
    Tobias Boettler
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
    J Immunol 191:5026-35. 2013
    ..The effect of the OX40 agonist was dependent on IL-2 signaling and the timing of OX40 stimulation. Collectively, our data demonstrate that excessive OX40 signaling can result in deleterious consequences in the setting of LCMV infection. ..
  4. pmc A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes
    Gisen Kim
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    J Immunol 190:1510-8. 2013
    ..Our data indicate that IL-27 has a crucial role in the inhibition of activation-induced cell death, thereby permitting Ag-driven T cell expansion...
  5. pmc Clinical targeting of the TNF and TNFR superfamilies
    Michael Croft
    Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
    Nat Rev Drug Discov 12:147-68. 2013
    ....
  6. pmc The microbiology of human hygiene and its impact on type 1 diabetes
    Nora M Chapman
    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
    Islets 4:253-61. 2012
    ....
  7. pmc OX40 facilitates control of a persistent virus infection
    Tobias Boettler
    Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America
    PLoS Pathog 8:e1002913. 2012
    ..Consequently, OX40-deficient mice fail to control LCMV clone 13 infection over time, highlighting the importance of this signaling pathway during persistent viral infection...
  8. pmc Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice
    Ekaterina K Koltsova
    Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
    Circ Res 111:1274-85. 2012
    ..The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown...
  9. pmc Novel transmembrane protein 126A (TMEM126A) couples with CD137L reverse signals in myeloid cells
    Jun Sang Bae
    Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130 701, Republic of Korea
    Cell Signal 24:2227-36. 2012
    ..These findings identify a novel molecule that bridges TNF family cytokines and pro-inflammatory cytokine secretion in myeloid cells...
  10. pmc TNF superfamily in inflammatory disease: translating basic insights
    Michael Croft
    La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, 9420 Athena Circle, La Jolla, CA 92037, USA
    Trends Immunol 33:144-52. 2012
    ..Here, we examine recent data regarding the potential of these molecules as targets for therapy of autoimmune and inflammatory disease...
  11. pmc Dispensable role for 4-1BB and 4-1BBL in development of vaccinia virus-specific CD8 T cells
    Yuan Zhao
    La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, 9420 Athena Circle, La Jolla, San Diego, CA 92037, USA
    Immunol Lett 141:220-6. 2012
    ..Thus, our data demonstrate that 4-1BB and 4-1BBL do not play a strong or dominant role in driving the generation of high frequencies of VACV-specific CD8 T cells...
  12. pmc Protein kinase C-η controls CTLA-4-mediated regulatory T cell function
    Kok Fai Kong
    1 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA 2
    Nat Immunol 15:465-72. 2014
    ..These results reveal a CTLA-4-PKC-η signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target. ..

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. Programming HIV Immunity for Broadly Neutralizing Antibodies by Vaccination
    Nancy L Haigwood; Fiscal Year: 2013
    ..abstract_text> ..
  3. Mechanisms of protein ubiquitination in regulating airway inflammation
    Yun Cai Liu; Fiscal Year: 2013
    ..Such studies will help to design novel therapeutic interventions for allergic diseases. ..
  4. Targeting Sirtuin-1 to enhance Foxp3+ regulatory T-cell function
    Ulf Beier; Fiscal Year: 2013
    ..Furthermore, it is important to learn more about the role of Sirtuin-1 in the immune system, as many investigators pursue Sirtuin-1 enhancement (diabetes mellitus, metabolic syndrome), or Sirtuin-1 suppression (certain cancers). ..
  5. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  6. Mechanisms and Enviromental Determinants of Rhinovirus Illness Severity
    James E Gern; Fiscal Year: 2013
    ..In this proposal, we will assemble a novel birth cohort to better farm effects on immune maturation and viral respiratory illnesses. The goal of this study is to identify new targets for the treatment and prevention of VRI. ..
  7. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  8. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  9. Autoimmunity Center of Excellence - Rochester
    R John Looney; Fiscal Year: 2013
    ..Therefore, we propose inhibiting CXCL13 using a human monoclonal antibody. The primary clinical outcome will again be adverse events. The primary mechanistic outcome will be changes in peripheral blood memory B cells. ..
  10. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  11. Antigen specificity in oral tolerance: the role of the anti-insulin B lymphocytes
    ZACHARY AARON FRANCIS KISTKA; Fiscal Year: 2013
    ....
  12. Cbl-b in T Cell Activation and Autoimmunity
    Jian Zhang; Fiscal Year: 2013
    ..A better understanding of cellular and molecular mechanisms of Cbl-b biological functions may lead to potential therapeutic approaches for autoimmune diseases and allergic asthma. ..