The overall goal of this project is to understand how the regulation of cell death is used to control immune responses in vivo. The proposed studies take advantage of a gene-targeted mouse train which lacks the alpha chain of the IL-2 receptor. These mice develop a lymphoproliferative disorder and autoimmunity, which correlates with a defect in the ability of T-cells to undergo apoptosis in response to activation. A variety of genes which regulate cell survival and death have been identified, including Fas, which is involved in activation-induced cell death, as well as members of the Bcl-2 family, which may participate in distinct cell survival pathways.
The aims of this application seek to identify the mechanisms of cell death regulation by IL-2R signals in vivo. Experiments are proposed to examine how genes involved in cell death and cell survival (including Fas, Fas ligand, Bcl-2, Bcl-X and Bax) may be regulated differently in lymphocytes from normal and IL-2R alpha deficient mice, and whether the Fas-mediated cell death pathway is functional. In addition, possible synergistic effects of Bcl-2 overexpression and dysregulation of IL-2Ralpha mutation. Finally, a system is proposed to study in detail how the fate of T-cells after antigen stimulation is affected by the IL-2Ralpha mutation. This system will utilize a T-cell receptor transgene introduced into the IL-2R alpha mutant background to facilitate uniform response to a defined antigen. Following immunization, t cell proliferation, cell death and differentiation into memory cells will be studied in detail. Regulation of cell death in the immune system is emerging as a major control point in both development of T- and B-cells and the regulation of the peripheral immune repertoire. The consequences of dysfunctional regulation of these pathways include autoimmunity and lymphoproliferative disorders, and have been implicated in the CD4+ T- cell destruction in HIV infection. Hence these studies are directly relevant to the pathogenesis of autoimmune diseases, lymphoid cancers and AIDS.
| Yang, Xuexian O; Doty, Raymond T; Hicks, Justin S et al. (2003) Regulation of T-cell receptor D beta 1 promoter by KLF5 through reiterated GC-rich motifs. Blood 101:4492-9 |
| Chuang, Peter I; Morefield, Samantha; Liu, Chien-Ying et al. (2002) Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1. Blood 99:3350-9 |
| Doty, Raymond T; Vanasse, Gary J; Disteche, Christine M et al. (2002) The leukemia-associated gene Mllt1/ENL: characterization of a murine homolog and demonstration of an essential role in embryonic development. Blood Cells Mol Dis 28:407-17 |
| Leung, D T; Morefield, S; Willerford, D M (2000) Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo. J Immunol 164:3527-34 |
| Zheng, L; Trageser, C L; Willerford, D M et al. (1998) T cell growth cytokines cause the superinduction of molecules mediating antigen-induced T lymphocyte death. J Immunol 160:763-9 |
| Nelson, B H; Willerford, D M (1998) Biology of the interleukin-2 receptor. Adv Immunol 70:1-81 |
