T cell activation requires a primary signal delivered by engagement of the T cell receptor (TCR) by MHC+ antigen complexes on antigen-presenting cells (APCs). In addition, a secondary signal delivered by the co-stimulatory molecules B7-1, B7-2 and CD40 on APCs, is also necessary for T cell activation. Amongst APCs, only dendritic cells (DCs) are thought to be capable of activating naive T lymphocytes. Microbial agents, such as lipopolysaccaride (LPS), are amongst the most important regulators of DC function. Engagement of Toll-like receptors (TLRs) by LPS and other microbial agents can lead to upregulation of cell surface expression of both MHC and co-stimulatory molecules on DCs, and the secretion of inflammatory cytokines. This process, often referred to as DC """"""""maturation"""""""", is thought to be essential for initiating productive T cell activation. While many recent studies have addressed mechanisms involved in controlling MHC cell surface expression in DCs, little is known about mechanisms involved in regulating co-stimulatory molecule (CM) surface expression in these cells. The goal of studies proposed here is to help understand this key aspect of immune regulation. To this end, we will investigate LPS-induced molecular mechanisms that eventually determine cell surface expression levels of the CMs B7-1, B7-2 and CD40 in DCs. A better understanding of these crucial mechanisms may provide insights for modulating expression of these molecules in therapeutic settings. An additional key goal of studies proposed here is to define molecular mechanisms involved in determining functional specificity of macrophage and DC-induced responses, in particular, those pertaining to regulation of CM expression.
The specific aims of this application are: (1) Transcriptional control of co-stimulatory molecule expression in DCs: role of NF-kB factors;(2) The role of post-transcriptional mechanisms in regulating co-stimulatory molecule cell surface expression in DCs;3) Molecular mechanisms involved in determining functional specificity of macrophages and DCs: regulation of CM expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059715-05
Application #
7588037
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2005-06-15
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$341,139
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Wang, Xingyu; Wang, Junmei; Zheng, Hong et al. (2014) Differential requirement for the IKK?/NF-?B signaling module in regulating TLR- versus RLR-induced type 1 IFN expression in dendritic cells. J Immunol 193:2538-45
Hopewell, Emily L; Bronk, Crystina C; Massengill, Michael et al. (2012) IKK?-induced inflammation impacts the kinetics but not the magnitude of the immune response to a viral vector. Eur J Immunol 42:681-7
Basagoudanavar, Suresh H; Thapa, Roshan J; Nogusa, Shoko et al. (2011) Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses. J Virol 85:2599-610
Balachandran, Siddharth; Beg, Amer A (2011) Defining emerging roles for NF-?B in antivirus responses: revisiting the interferon-? enhanceosome paradigm. PLoS Pathog 7:e1002165
Vang, Kieng B; Yang, Jianying; Pagán, Antonio J et al. (2010) Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 184:4074-7
Wang, Junmei; Basagoudanavar, Suresh H; Wang, Xingyu et al. (2010) NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication. J Immunol 185:1720-9
Plumlee, Courtney R; Lee, Carolyn; Beg, Amer A et al. (2009) Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem 284:30058-66
Valenzuela, Javier O; Iclozan, Cristina; Hossain, Mohammad S et al. (2009) PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice. J Clin Invest 119:3774-86
Wang, Xingyu; Hussain, Sofia; Wang, Emilie-Jeanne et al. (2007) Lack of essential role of NF-kappa B p50, RelA, and cRel subunits in virus-induced type 1 IFN expression. J Immunol 178:6770-6
Wang, Junmei; Wang, Xingyu; Hussain, Sofia et al. (2007) Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells. J Immunol 178:6777-88