Abstract 5472: Expression Of TCTP Antisense In CD4+CD25High Regulatory T Cells Weakens The Cell Survival And Aggravates Vascular Inflammation
Suppression of atherosclerosis and adaptive immune responses by CD4+CD25high regulatory T cells (Tregs) has been reported. However, the role of Tregs in suppressing adaptive immunity-independent acute vascular inflammation remains poorly defined. In addition, the question of whether signaling pathways in regulating Treg apoptosis can be modulated for regulation of inflammation is less well known. We examined our hypotheses that anti-apoptotic protein translationally controlled tumor protein (TCTP) expression in Tregs is critical for Treg survival and homeostasis, and that modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that lower TCTP expression in Tregs than in CD4+CD25-T cells was associated with the higher susceptibility of Tregs to apoptosis induced by interleukin-2 (IL-2, a Treg survival cytokine) withdrawal. To determine whether the expression of TCTP in Tregs is critical for Treg generation and survival, we established a Tregs-specific TCTP antisense transgenic mouse model. Overexpression of TCTP antisense in Tregs in TCTP transgenic mice led to decreased positive selection of CD25high thymic Tregs and reduced survival of peripheral Tregs. In addition, TCTP antisense transgene conferred higher susceptibility of Tregs to apoptosis induced by IL-2 withdrawal than wild-type Tregs, which was suppressed by exogenous supply of IL-2, suggesting that IL-2 promotes Treg survival at least partially due to promoting TCTP expression. Finally, decreased expression of TCTP in Tregs aggravated experimental vascular inflammation, presumably due to increased Treg apoptosis and failure of decreased Tregs in suppressing inflammatory cells and immune cells. The result is correlated to our previous reports that the overexpression of TCTP antisense cDNA knocks down the expression of anti-apoptotic TCTP protein and promotes T cell apoptosis, and that higher expression of pro-apoptotic protein Bax in Tregs increases vascular inflammation. These results suggest that Tregs suppress acute vascular inflammation, and that the modulation of Tregs apoptosis/survival may be used as a new therapeutic approach for treating inflammatory cardiovascular diseases.