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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
United States
Zip Code
Burrack, Adam L; Malhotra, Deepali; Dileepan, Thamotharampillai et al. (2018) Cutting Edge: Allograft Rejection Is Associated with Weak T Cell Responses to Many Different Graft Leukocyte-Derived Peptides. J Immunol 200:477-482
Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2018) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol 84:2-10
Osum, Kevin C; Burrack, Adam L; Martinov, Tijana et al. (2018) Interferon-gamma drives programmed death-ligand 1 expression on islet ? cells to limit T cell function during autoimmune diabetes. Sci Rep 8:8295
Ruscher, Roland; Hogquist, Kristin A (2018) Intravenous Labeling and Analysis of the Content of Thymic Perivascular Spaces. Bio Protoc 8:
Kotov, Dmitri I; Kotov, Jessica A; Goldberg, Michael F et al. (2018) Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. J Immunol 200:2004-2012
Burrack, Adam L; Martinov, Tijana; Fife, Brian T (2017) T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) 8:343
Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779
Schmiel, Shirdi E; Yang, Jessica A; Jenkins, Marc K et al. (2017) Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination. J Immunol 198:623-628
Spanier, Justin A; Sahli, Nathanael L; Wilson, Joseph C et al. (2017) Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. Diabetes 66:3051-3060
Karunakaran, Karuna P; Yu, Hong; Jiang, Xiaozhou et al. (2017) Identification of MHC-Bound Peptides from Dendritic Cells Infected with Salmonella enterica Strain SL1344: Implications for a Nontyphoidal Salmonella Vaccine. J Proteome Res 16:298-306

Showing the most recent 10 out of 136 publications