ANTIGEN-INDUCED APOPTOSIS (PROPRIOCIDAL REGULATION) OF MATURE T LYMPHOCYTES

这个项目是基于我们的发现，刺激抗原 细胞暴露于有丝分裂后的成熟T细胞受体 IL-2等淋巴因子可诱导细胞程序性死亡 或细胞凋亡(固有的杀伤性调节)。我们感兴趣的是 本体法的调控机制。我们也在研究这是否 机制可以解释某些免疫“抑制”现象 以及这一机制如何在 针对人类疾病的各种免疫调节策略正在尝试之中。 我们研究了在高剂量下控制细胞凋亡的参数。 压制。我们发现抑制与IL-2受体有关 表达和增殖增加，这是一个函数 抗原提呈效率。我们还证明了T 来自P53生殖系缺陷小鼠的细胞母细胞 抑癌基因对TCR诱导的细胞凋亡敏感 与野生型来源的T细胞程度相同。相比之下，P53-/-T 拓扑异构酶保护淋巴细胞免于死亡 II类抑制剂依托泊苷和替尼平苷。我们还对表达式进行了分析 在多种细胞类型中由P53诱导的bax和p21的表达，并发挥作用。 在细胞凋亡中的作用。我们发现bax和p21mRNAs在 反义寡核苷酸刺激T细胞后的P53依赖方式 CD3epsilon单抗或用拓扑异构酶抑制剂治疗。这 提示当T细胞增殖时，P53途径被上调 是通过T细胞受体刺激的，但T细胞凋亡可以 通过P53非依赖途径发生。 目前，我们正在探索本体性杀伤性细胞凋亡在 由不同途径给予的抗原诱导的耐受性包括 静脉或腹膜内注射或口服。口头的 耐受性被认为是对抗各种自身免疫的一种手段。 通过刺激特殊的抑制细胞而引起的疾病。我们是 研究口服耐受是否通过引起免疫应答而影响免疫应答 通过本体杀伤机制诱导T细胞的凋亡。最后，在艾滋病方面，我们有 我一直在研究各种类型的T细胞死亡。我们是 检验假设CD8T选定群体的丧失 对杀死受感染的CD4细胞至关重要的细胞可能通过 本体主义杀伤力机制。这样的事件可能会削弱免疫力 对艾滋病毒的反应和导致艾滋病疾病的进展。

This project is based on our discovery that stimulation of the antigen receptor of mature T cells following exposure of the cells to mitogenic lymphokines such as IL-2 leads to the induction of programmed cell death or apoptosis (propriocidal regulation). We are interested in the mechanism of propriocidal regulation. We are also studying whether this mechanism can explain certain phenomenon of immunological "suppression" that have been previously studied and how this mechanism plays a role in various immunomodulatory strategies being attempted for human disease. We have studied the parameters that control apoptosis during high dose suppression. We found that suppression correlates with IL-2 receptor expression and increased proliferation and was a function of the efficiency of antigen presentation. We have also demonstrated that T cell blasts derived from mice containing a germline deficiency of the p53 tumor suppressor gene are susceptible to TCR-induced apoptosis to the same degree as wild type derived T cells. By contrast, p53-/-T lymphocyte blasts are protected from death caused by the topoisomerase II inhibitors etoposide and teniposide. We also analyzed the expression of Bax and p21 which are induced by p53 in many cell-types and play a role in apoptosis. We found that bax and p21 mRNAs are upregulated in a p53-dependent manner in T cell blasts following stimulation with anti- CD3epsilon mAb or treatment with the topoisomerase inhibitors. This indicates that the p53-pathway is upregulated when proliferating T cells are stimulated through the T cell receptor, but T cell apoptosis can occur via a p53 independent pathway. Currently, we are exploring the role of propriocidal apoptosis in tolerance induced by antigen given by different routes including intravenous or intraperitoneal injection or oral administration. Oral tolerance has been proposed as a means to combat various autoimmune diseases by the stimulation of specialized suppressor cells. We are studying whether oral tolerance effects immune responsiveness by causing T cell apoptosis by the propriocidal mechanism. Finally, in AIDS we have been studying the various types of T cell death that occur. We are testing the hypothesis that the loss of selected populations of CD8 T cells that are vital for killing infected CD4 cells may occur by the propriocidal mechanism. Such an event could debilitate the immune response against HIV and lead to progression of disease in AIDS.