Program Director/Principal Investigator (Last, First, Middle): Gajewski, Thomas F. 1R01 AI080745-01A1 Revised Abstract Section Evidence suggests that one mechanism of peripheral immunologic tolerance occurs through the mediated Ras activation. Recent data have indicated that upregulated expression of lipid kinases process of T cell anergy. Anergic I cells have been characterized to have a defect in TCR/CD28- L]' (Ti 'D- of the diacylglycerol kinase (DGK) family, in particular DGK-u, participate in the suppression of targeted genes in the post-thymic I cell compartment. Tg T cells in vitro, and transgenic mice expressing key DGK-u mutants in peripheral T cells will ascertained. Mutants of DGK-z will be analyzed functionally using adenoviral vectors and CAR the second specific aim, the functional adenoviruses for EGR2 expression, and a Cre adenovirus for conditional deletion of EGR2 in employed using the CAR Tg system. with a focus centered on EGR2. Novel tools for the genetic manipulation of primary T cells will be tolerance. detailed understanding of DGKs and EGR2 in binding sites in the putative DGK-ci promoter. increased expression of the transcriptional regulator EGR2, and we have identified EGR-farnily RasGRP-mediated Ras activation in the anergic state. peripheral I cells. Supportive data will come from ChIP assays and gene expression profiling. immunologic tolerance in disease situations. peripheral tolerance, paving the way for development of pharmacologic agents to manipulate addressed. autoimmunity and anergy susceptibility, and possible improved tumor rejection in vivo will be These experiments will take advantage of the Cre-adenovirus approach to delete conditionally elimination of EGR2 directly in peripheral T cells on peripheral tolerance will be investigated. be studied for altered immune function in vivo. In the first specific aim, the transcriptional regulation of the DGK-u will be elucidated, In total, this work will characterize in detail a critical pathway in the control of This includes transcriptional reporter adenoviral vectors, role of DGK-u tyrosine phosphorylabon will The major goal of this proposal is to gain a In the third specific aim, the consequence of controlling T cell activation and peripheral T cell activation properties, in vivo Correlating with these changes is coo be In 0-0 ADZ 0(Q j-<-0 c-0 .Ti U,0 ._0 ... u?r tow 5a' ?c' OUP O-0 N-0 0-0 V,12 oar aux. :E, -'1 .., (gyp a?fl' coo COD m='(Dm o03?-' _=c? 3m03 l17 CDG'O COB 111
T cell anergy is a mechanism by which the immune system regulates tolerance to tissues, a process relevant for cancer as well as for autoimmunity. The overall goal of this proposal is to understand in detail the critical molecular changes that we believe control whether T cells become anergic or not. The results of these experiments should pave the way for the development of pharmacologic approaches for the manipulation of immunologic tolerance in relevant disease situations in vivo, such as autoimmunity and transplantation (where tolerance is desired), or cancer and chronic viral infections (where tolerance needs to be overcome). <'< '.U cc's
| Zheng, Yan; Zha, Yuanyuan; Spaapen, Robbert M et al. (2013) Egr2-dependent gene expression profiling and ChIP-Seq reveal novel biologic targets in T cell anergy. Mol Immunol 55:283-91 |
| Zheng, Yan; Zha, Yuanyuan; Driessens, Gregory et al. (2012) Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J Exp Med 209:2157-63 |
