Abstract

Our recent studies have indicated a critical role for the T-box transcription factor T-bet in the regulation of class switching in B cells as well as in autoantibody production in systemic autoimmune disease: T-bet deficiency dramatically impairs IFN-gamma-mediated class switching to IgG2a as well as the generation of autoantibodies in the MRL/Ipr murine model of lupus, and conversely enhances IL-4-related responses, such as IgE production. Using genetically mutant mice and in vitro cell culture systems, we propose here to further delineate the role of T-bet in both conventional and autoimmune B cell responses by defining and characterizing the molecular pathways in which this novel pathogenic and therapeutic target regulates isotype switching, cellular proliferation, and the activation of mature, autoreactive B lymphocytes. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057471-04
Application #
6999868
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Peyman, John A
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$244,125
Indirect Cost

  Institution

Name
Roche Palo Alto, LLC
Department
Type
DUNS #
063548663
City
Palo Alto
State
CA
Country
United States
Zip Code
94304

  Publications

Peng, Stanford L (2010) Forkhead transcription factors in chronic inflammation. Int J Biochem Cell Biol 42:482-5
Chen, Jing; Limon, Jose J; Blanc, Caroline et al. (2010) Foxo1 regulates marginal zone B-cell development. Eur J Immunol 40:1890-6
Gubbels Bupp, Melanie R; Edwards, Bonnie; Guo, Caiying et al. (2009) T cells require Foxo1 to populate the peripheral lymphoid organs. Eur J Immunol 39:2991-9
Lin, Ling; Peng, Stanford L (2006) Coordination of NF-kappaB and NFAT antagonism by the forkhead transcription factor Foxd1. J Immunol 176:4793-803
Wu, Xiaobo; Peng, Stanford L (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54:336-42
Lin, Ling; Brody, Steven L; Peng, Stanford L (2005) Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6. J Immunol 175:951-8
Lin, Ling; Peng, Stanford L (2005) Interleukin-18 receptor signaling is not required for autoantibody production and end-organ disease in murine lupus. Arthritis Rheum 52:984-6
Peng, Stanford L (2005) Signaling in B cells via Toll-like receptors. Curr Opin Immunol 17:230-6
Harris, David P; Goodrich, Stephen; Gerth, Andrea J et al. (2005) Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor. J Immunol 174:6781-90
Jonsson, Helena; Allen, Paul; Peng, Stanford L (2005) Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat Med 11:666-71

Showing the most recent 10 out of 21 publications