| Most cells in the body are in a resting state and undergo cell cycle progression only upon growth factor stimulation or activation. While much research on proliferation and activation has been performed, we know very little about signals that maintain quiescent cells in G0, preventing cell cycle entry or apoptosis. DPP2 is a serine protease that plays an essential role in the survival of G0 cells. In this thesis, the pathways of apoptosis induction in quiescent T cells and fibroblasts mediated by inhibition or down-regulation of Dipeptidyl Peptidase 2 (DPP2) have been explored. A decrease in DPP2 activity results in the exit of resting cells from G 0, accompanied by a decrease in p130, p27Kip1 and p21 Cip1 protein levels. In addition, inhibition of DPP2 in cells exhibit an increase in early G1/S progressors, with increases in the levels of retinoblastoma (pRb), p107 and cyclin D proteins. Furthermore, decrease of DPP2 activity leads to an increase in c-Myc and a decrease in Bcl-2, two events that have been associated with apoptosis induction. This apoptosis by DPP2 downregulation is prevented in p53-/- cells or by ectopic expression of proteins that suppress p53 or c-Myc activity. Thus, DPP2 is essential for maintaining lymphocytes and fibroblasts in G0, and its inhibition results in apoptosis mediated by induction of c-Myc and p53.;In the absence of this protease activity quiescent lymphocytes drift into G1 and die by apoptosis, due to deregulated entry into the cell cycle. Mice where DPP2 levels were decreased (knock down, kd) by constitutive or conditional expression of shRNA were generated. Constitutive kd DPP2 mice were embryonic lethal, therefore conditional DPP2 kd mice were crossed with Lck-Cre transgenic mice, resulting in down-regulation of DPP2 in T cells, were characterized. Surprisingly, the overall development of T cells progressed normally in these mice; however, the T cells were hyperactive when stimulated in vitro. The cytokine profile indicates that the CD8+ and CD4+ cells differentiated mainly into IL-17 producing effector and Th17 cells, which have been shown to mount inflammatory autoimmune responses. In agreement with this, kd DPP2-Lck mice have elevated serum levels of autoantibodies. Thus, DPP2 may be an important factor in preventing autoimmunity and tissue inflammation in vivo.;Collectively, these results strongly suggest that DPP2 is an essential protease that is involved intricately in the G0/G1 transition in T cells, preventing their differentiation into IL-17 secreting cells. |
