The molecular and cellular mechanisms by which CD4+CD25+FoxP3+ T cells are induced and by which they inhibit induction of autoimmunity have not been elucidated. The role of this subset of T cells in the regulation of EAE, an animal model of Multiple Sclerosis (MS), is just beginning to be investigated. To study FoxP3+ T cells at the single cell level in vivo, we specifically introduced the green fluorescent protein (GFP) into the endogenous FoxpS genomic locus by homologous recombination and generated a FoxPS knock-in mouse (FoxPSKI). In the FoxpSKI mice and with the use of MOG lAb specific tetramer, we followed in vivo the generation of MOG specific regulatory cells (T-regs) and found that MOG specific T-regs accumulate in the central nervous system (CNS) during the course of EAE, and produced IL-10 and unexpectedly IFN-g. To study the function of T-regs in EAE, we will take advantage of mice in which a DTR/GFP (Diphteria Toxin Receptor fused with the Green Fluorescent Protein) reporter has been introduced into the endogenous FoxPS locus, allowing in vivo conditional depletion of FoxPS expressing cells through administration of diphteria toxin. Using these mice we will be able to study the generation, trafficking and in vivo function of MOG specific T-regs, by deleting them at different stages of EAE. We also discovered that CD4+ T cells can differentiate in vitro into either pathogenic Th17 cells in the presence of TGF-b plus IL-6 or T-reg in the presence of TGF-b alone. These results suggest the existence of reciprocity in the function of these two subsets in vivo, and that they may regulate each other. However, whether the inflammatory milieu and pathogenic Th17 cells can modulate the generation and the suppressive activity of T-reg cells has not been elucidated. To address these important questions related to the interplay between Th17 and T-reg, we have generated a novel reporter mouse in which IL-17 expressing cells IL-17 can be followed by the Red Fluorescent Protein (RFP) and these cells can be conditionally depleted through administration of diphteria toxin. Based on our novel reagents and preliminary data, we have designed experiments to directly answer the following questions:
Aim1 : What is the origin and function of different subsets of MOG specific Tregs? Aim2: What is the role of IL-6 on Treg function in EAE? Aim3: What is the interplay between T-regs and Th17inEAE?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073542-05
Application #
7778249
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$426,110
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Lazarevic, Vanja; Chen, Xi; Shim, Jae-Hyuck et al. (2011) T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding ROR?t. Nat Immunol 12:96-104
Riol-Blanco, Lorena; Lazarevic, Vanja; Awasthi, Amit et al. (2010) IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections. J Immunol 184:1710-20
Petermann, Franziska; Rothhammer, Veit; Claussen, Malte C et al. (2010) ?? T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 33:351-63
Kyttaris, Vasileios C; Zhang, Zheng; Kuchroo, Vijay K et al. (2010) Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol 184:4605-9
Tartar, Danielle M; VanMorlan, Amie M; Wan, Xiaoxiao et al. (2010) FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. J Immunol 184:3377-85
Quintana, Francisco J; Iglesias, Antonio H; Farez, Mauricio F et al. (2010) Adaptive autoimmunity and Foxp3-based immunoregulation in zebrafish. PLoS One 5:e9478
Edgerton, Colin; Crispín, José C; Moratz, Chantal M et al. (2009) IL-17 producing CD4+ T cells mediate accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice. Clin Immunol 130:313-21
Araki, Manabu; Chung, Denise; Liu, Sue et al. (2009) Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. J Immunol 183:5146-57
Ochs, Hans D; Oukka, Mohamed; Torgerson, Troy R (2009) TH17 cells and regulatory T cells in primary immunodeficiency diseases. J Allergy Clin Immunol 123:977-83; quiz 984-5
Elyaman, Wassim; Bradshaw, Elizabeth M; Uyttenhove, Catherine et al. (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885-90

Showing the most recent 10 out of 27 publications