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.
