Tolerance induction in T lymphocytes is a well-documented property of the mammalian immune system that insures immune responses are not mounted to self-antigens. Although there are several mechanisms that can lead to tolerance, it is clear that in some cases the potentially reactive immune cells are not destroyed but instead are blocked from undergoing normal cell division and remain in a state of anergy. These studies will explore the molecular basis of this form of tolerance through use of a model system in which mouse helper T lymphocytes (Th1 cells) are tolerized to an antigen (keyhole limpet hemocyanin) in the presence of n-butyrate, a pharmacological inhibitor of the cell cycle. Preliminary findings have shown that n-butyrate-induced anergy alters expression of certain G1 cell cycle regulatory proteins, namely specific cyclin-dependent kinase inhibitors (CDKIs). The hypothesis to be tested is that there is sustained expression of one CDKI, designated p27, and transcriptional up-regulation of a second CDKI, designated p21, that leads to anergy. As one objective, experiments will be conducted to confirm that both the protein levels and inhibitory activities of these CDKIs are increased in anergic Th1 cells compared to control cells. Levels and activities of the target G1 cyclins and cyclin-dependent kinases will also be assessed. As a second objective, preliminary experiments will examine tolerance induction in cells genetically altered to express either increased or lowered levels of the CDKIs. The studies will provide novel information on a mechanism of tolerance induction by examining a previously undocumented connection between regulatory proteins of the cell cycle and T helper cell anergy. The studies will provide information that may be relevant to other and more generalized mechanisms of tolerance induction in the intact animal.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Jermelina Tupas
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University of Arkansas Medical Sciences Campus
Little Rock
United States
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