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) andeither 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 aretolerant long-term.
Under Aim 1, these 'signal 3 tolerant' cells will be further characterized with respect totheir phenotype and functional capacity.
Under Aim 2, experiments will be done to determine the mechanisticbasis for the non-responsiveness. Preliminary evidence strongly suggests that the non-responsivenessresults 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 statewe have termed activation-induced non-responsiveness (AINR) in which they lose the ability to produce IL-2to support continued expansion (a form of anergy).
Under Aim 3, experiments will be done to determinewhen the conversion from AINR to responsive memory cells occurs, and define the mechanistic basis for thisconversion. It is expected that the results of these studies will contribute to a better understanding of thebasic mechanisms responsible for inducing peripheral tolerance in CDST cells, and suggest ways of avoidingor reversing tolerance for therapy of tumors and viral diseases.
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