FUNCTIONAL CHARACTERIZATION OF ANERGIC HELPER T CELLS

无能辅助 T 细胞的功能表征

• 批准号: 6201189
• 负责人: Daniel L Mueller
• 金额: $ 11.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201189
• 关键词: T cell receptor; anergy; arthritis; biological signal transduction; disease /disorder model; flow cytometry; genetically modified animals; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; ovalbumin; passive immunization

Immune tolerance to peripheral self-antigens in vivo depends on the combined effects of several mechanisms: clonal anergy, deletion, suppression, and clonal ignorance. Each mechanism is antigen- specific; therefore, an understanding of their underlying nature could serve as a foundation for the design of rational strategies for the treatment of autoimmune diseases. Work under this project in the past has focused on the regulation of immune responsiveness by the clonal anergy mechanism using cloned CD4 plus T cells. Our experiments revealed that clonal anergy inhibits T-cell growth not only by blocking secretion of an autocrine growth factor, but also by blocking the up-regulation of lymphokine responsiveness. Clonal anergy was found to be associated with a defect that prevents signals from reaching the MAP kinases ERK and JNK, and that results in reduced induction of the AP-1 proteins c-Fos and JunB, both of which are critical for transactivation at the 5' IL-2 gene enhancer. NAFTp, on the other hand, could be activated in anergic T cells. Consistent with this, lymphokines other than IL-2 (e.g., IL-4) could be induced to various degrees, as could CD40L expression, and anergic T cells could still stimulate B cells to grow and differentiate in vitro. Finally, the study of these cloned T cells led to an understanding of the regulation of the death-repressor proteins Bcl-2 and Bcl-x. More recent work has established an in vivo model of T-cell tolerance with features indicative of the induction of clonal anergy. TCR transgenic T cells recovered from animals exposed to soluble antigen in the absence of adjuvant demonstrate an inability to produce IL-2. In the experiments proposed in this application, these tolerant T cells will be studied both in vitro and in vivo for evidence of signal transduction defects and to assess their capacity to participate in both antibody- and cell-mediate immune responses. Furthermore, the survival characteristics of the tolerant T cells will be examined, and this will be correlated with their expression of various death-repressor and -effector proteins. Finally, an antigen-induced arthritis model will test the capacity of this method of T-cell tolerance induction to prevent the development of an inflammatory disease. The data obtained will expand our understanding of the regulation of peripheral self-tolerance, as pursued under this program project, as well as serve as a basic for the development of therapeutic approaches to the problem of human autoimmune disease.

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