Regulation of T cell anergy by caspase 3
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T cell mediated immunity relies on the recognition of potentially harmful antigens by the T cell receptor (TCR). Random rearrangements of gene segments at the TCR locus generate T lymphocytes that uniquely recognize foreign antigens but also generate dangerous self-reactive T cells. Mechanisms of central and peripheral tolerance are required to avoid autoimmune events. Anergy is one mechanism enabling peripheral tolerance that leads to the functional inactivation of self-reactive T cells. Anergy is induced by partial engagement of the TCR in the absence of costimulation, and results in a profound decrease in IL-2 production and T cell proliferation, even upon subsequent full stimulation.;During anergy induction, calcium-mediated signals upregulate the expression of a specific set of genes that will impose the hyporesponsive state that characterizes anergic T cells. Casp3 is one of the genes activated during anergy induction. Caspase 3 is a key effector member of the caspase family of cysteine proteases important not only in apoptosis, but also in other important cellular events, including cell proliferation and differentiation.;The overall goal of my thesis project is to elucidate the role of caspase 3 in the establishment of T cell anergy. Our results show that the upregulation of caspase 3 expression in anergic cells is also accompanied by activation of this protease without induction of apoptosis. Confirming the contribution of caspase 3 activity to the induction and maintenance of T cell anergy, we show that T cells in which caspase 3 expression is specifically blocked by RNA interference and T cells from casp3-/- mice show profound impairment in the induction of T cell anergy. In anergic T cells, activated caspase 3 associates to the plasma membrane, where it can cleave and inactivate proteins such as GADS and Vav1, contributing to the blockade of the TCR signaling that characterizes T cell anergy.;Our findings provide new data on how a key protease, caspase 3, is specifically activated and localized to interfere directly with the signaling events initiated at the immune synapse. Our work adds new insight on the non-apoptotic roles of caspases and the mechanisms of inactivation of self-reactive T cells.
- Theses and Dissertations