REGULATION OF APOPTOSIS IN THYMOCYTES AND T LYMPHOCYTES

T淋巴细胞群的区分能力 “自我”和“非我”是免疫的一个中心特征。 系统。在T淋巴细胞谱系中，谱系选择需要 主要在胸腺内T细胞的发育过程中 他们未成熟的骨髓源祖细胞，但也可能继续 对周围组织中成熟的T细胞进行手术。两者都有 正选择和负选择取决于消除未观察到的 一种被称为细胞凋亡的程序性细胞死亡形式。 了解这些细胞中的凋亡性死亡的调节 因此对未来T细胞的治疗操作至关重要 曲目。 我们将研究一种新鉴定的16kD蛋白的作用 (为了方便起见，这里称为P16)在胸腺细胞和 T细胞凋亡。P16与Bax成员共享一个抗原表位 属于Bc l-2基因家族。BCL-2家族成员在肿瘤发生发展中起着核心作用 调节多种细胞类型的凋亡，包括T淋巴细胞。 在正常淋巴细胞中，p16也与Bax有物理联系。基座 根据这些观察结果，我们推测p166是一种抗细胞凋亡剂。 BCL-2家族成员通过与Bax和Bax的异源二聚起作用 抑制淋巴细胞中Bax的促凋亡活性。我们会 通过调查来测试这一工作模式：(1)遗传 P16与Bcl2家族的关系：(2)发育 P16表达的调控；(3)P16下调的机制。 以及(4)P16在调节T细胞中的作用 细胞发育和细胞凋亡。

The ability of the T lymphocyte population to distinguish between "self" and "non-self" is a central characteristic of the immune system. In the T lymphocyte lineage, repertoire selection takes place primarily during the intrathymic development of T cells from their immature bone marrow-derived progenitors, but may also continue to operate on mature T cells in the peripheral tissues. Both positive and negative selection depend on the elimination of unwatned cells by a form of programmed cell death called apoptosis. Understanding the regulation of apoptotic death in these cells is thus critical to future therapeutic manipulation of the T cell repertoire. We will investigate the role of a newly characterized 16kD protein (called "P16" here, for convience) in the regulation of thymocyte and T cell apoptosis. P16 shares an antigenic epitope with Bax, a member of the Bcl-2 gene family. Bcl-2 family members are central to the regulation of apoptosis in many cell types, including T lymphocytes. P16 also physically associates with Bax in normal lymphocytes. Based on these observations, we postulate that P166 is an anti-apoptotic Bcl-2 family member that acts by heterodimerizing with Bax and inhibiting the pro-apoptotic activity of Bax in lymphocytes. We will test this working model by investigating: (1) the genetic relationship of P16 to the Bcl-2 family; (2) the developmental regulation of P16 expression; (3) the mechanism of P16 down- modulation during apoptosis; and (4) the role of P16 in regulating T cell development and apoptosis.