Previous work under this grant has defined two forms of peripheral tolerance that can develop in CDST cells. Naive CDST cells require three signals for full activation;antigen, costimulatory ligand (usually 67-1,2) and either IL-12 or Type IIFN. Antigen recognition in the absence of a 'signal 3'cytokine stimulates proliferation, but the differentiation program leading to effector function and memory does not occur, and the cells are tolerant long-term.
Under Aim 1, these 'signal 3 tolerant'cells will be further characterized with respect to their phenotype and functional capacity.
Under Aim 2, experiments will be done to determine the mechanistic basis for the non-responsiveness. Preliminary evidence strongly suggests that the non-responsiveness results from a failure of critical gene loci to undergo chromatin remodeling in the absence of a signal from IL- 12/IFN-a. A second form of tolerance can occur when CDST cells become fully activated, but enter a state we have termed activation-induced non-responsiveness (AINR) in which they lose the ability to produce IL-2 to support continued expansion (a form of anergy).
Under Aim 3, experiments will be done to determine when the conversion from AINR to responsive memory cells occurs, and define the mechanistic basis for this conversion. It is expected that the results of these studies will contribute to a better understanding of the basic mechanisms responsible for inducing peripheral tolerance in CDST cells, and suggest ways of avoiding or reversing tolerance for therapy of tumors and viral diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035296-19
Application #
8308581
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2011-08-01
Project End
2013-05-14
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
19
Fiscal Year
2011
Total Cost
$340,724
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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