: A productive T lymphocyte response to antigen requires the activation of two signaling pathways, involving signals generated by the interactions between the T-cell receptor (TCR) with antigenic peptide presented on antigen-presenting cells (APCs) and the signal mediated by the binding of the accessory receptor CD28 with its ligand B7. Although the requirement for CD28 co-stimulation has been the subject of intensive and extensive investigation, the molecular nature of this co-stimulatory signal is unknown. Some models have identified distinct kinase cascades initiated by either the ICR or CD28, while other models have focused on the convergence of TCR/CD28 signals on particular kinase cascades. One pathway which can mediate the synergistic responses that characterize CD28 co-stimulation is the MAP kinase (ERK) cascade. The activation of the MAP kinase ERK following CD28 co-stimulation is required for IL-2 production and proliferation of responding T lymphocytes. ERK activation in T lymphocytes is regulated by two antagonistic small G proteins: Ras and Rap1. Ras activation is required for ERK activation, while Rap1 antagonizes Ras signaling. Antigen recognition by T-cells in the absence of CD28 co-stimulation is characterized by impaired ERK activation and both decreased IL-2 production and diminished proliferation. This functional unresponsiveness results in the inability to respond to subsequent co-stimulatory signals and is termed clonal anergy. Rap1 is constitutively activated in certain states of I cell anergy or this unresponsiveness may account for the diminished ERK activity and decreased IL-2 production seen in anergic T-cells. In this proposal, we will test the hypothesis that Rap1 is activated by ICR ligation in normal I cells and consequently limits I cell activation through the ICR in the absence of co-stimulation. In addition, we will test the hypothesis that CD28 co-stimulation achieves increased ERK activation, IL-2 production and proliferation by blocking Rap1 activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047337-05
Application #
6867359
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nabavi, Nasrin N
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$302,000
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Stork, Philip J S; Dillon, Tara J (2005) Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. Blood 106:2952-61
Dillon, Tara J; Carey, Kendall D; Wetzel, Scott A et al. (2005) Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4. Mol Cell Biol 25:4117-28
Dillon, Tara J; Karpitski, Vladamir; Wetzel, Scott A et al. (2003) Ectopic B-Raf expression enhances extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy. J Biol Chem 278:35940-9