After stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be deter- IntroductionMaintaining the homeostasis of different cell types in the immune system is critical for the prevention of immune dysregulation, such as uncontrolled inflammation. DCs are the most efficient antigenpresenting cells that process and present antigens to initiate the activation of antigen-specific lymphocytes. 1-5 DCs represent a small population in the immune system and comprise approximately 1% of the total cell population in lymphoid organs. 6 However, DC homeostasis has a major impact on the immune system. It has been shown that inhibition of Fas signaling in DCs induces DC accumulation and onset of autoimmune diseases. 7,8 Although temporary deletion of DCs decreases immune responses, 9 constitutive ablation of DCs by DC-specific expression of DTA in CD11c-DTA transgenic mice has been shown to induce fatal autoimmune and inflammatory responses. 10 This suggests that homeostasis of DCs plays a major role in maintaining a balanced immune system. Activated antigen-specific T cells may promote the clearance of antigen-bearing DCs in vivo. 11 Interestingly, it has been shown that activated antigen-specific T cells are capable of killing exogenously administrated antigen-bearing DCs through perforin in vivo, thereby limiting antigen-specific T-cell responses. 12-17 Inhibition of Fas signaling or deletion of Fas in DCs leads to DC accumulation and the development of autoimmunity. 7,8 However, a role for perforin in controlling DC homeostasis in the absence of infections remains to be established.Haemophagocytic lymphohistiocytosis (HLH) is an inflammatory disorder that displays hypercytokinaemia and uncontrolled activation of T cells and macrophages. [18][19][20][21] In humans, mutations in perforin or other genes that affect perforin-dependent cytotoxicity were first identified in patients with familial HLH. [22][23][24][25][26] Perforin is a cytolytic molecule secreted by cytotoxic T cells and NK cells. [27][28][29][30] Knockout of perforin in mice has been shown to impair the cytolytic activity of T cells toward targets cells. 31,32 Although perforin Ϫ/Ϫ mice do not spontaneously develop inflammation, infection of these mice with LCMV induced uncontrolled T-cell activation, especially in CD8 ϩ T cells, 33-37 leading to the development of inflammatory symptoms resembling familial HLH. 38 Perforin-deficient mice mount CD8 ϩ T-cell mediated and IFN-␥-dependent lethal inflammation in response to infection by LCMV. 38 Increased T-cell activation has been linked to elevated antigen presentation in perforin-deficient mice during LCMV infection. 39 This suggests that deficiency in perforin synergizes with other factors du...

Dehydroartemisinin (DHA) is an effective anti-malaria agent. Fortilin is an anti-apoptotic molecule overexpressed in many human cancers. Here, we show that DHA binds human fortilin, increases the ubiquitination of fortilin, shortens fortilinÕs half-life in a proteasome-dependent fashion, and reduces cellular levels of fortilin in varieties of cells. DHA induced DNA fragmentation in U2OS cells in a fortilin-dependent manner. The fortilin-knocked-down cells were less susceptible-and fortilinoverexpressing cells more susceptible-to DHA than were wild-type cells, suggesting that apoptotic effects of DHA areat least partly-conferred through fortilin. Together, these data suggest that fortilin is a molecular target of DHA. DHA and its derivative may prove to be viable anti-cancer agents in fortilinoverexpressing cancers.

No abstract

The fate of dendritic cells (DCs) after Ag presentation may be DC subset-specific and controlled by many factors. The role of activation-induced apoptosis in regulating DC function is not clear. We investigated the fate of cutaneous DCs (cDCs), specifically Langerhans cells (LCs), and observed that they undergo apoptosis after successful Ag presentation to CD4 T cells. Caspase-specific inhibitors revealed that LC lines use a type II apoptosis pathway in response to CD4 T cells. In support of this, BH3-interacting domain (Bid) protein was present at high levels and specifically cleaved in the presence of Ag-specific T cells. Significant resistance to apoptosis by OT-2 CD4 cells was also observed for Bid knockout (KO) LCs in vitro. To test whether Bid was required to regulate LC function in vivo, we measured contact sensitization and topical immunization responses in Bid KO mice and observed markedly enhanced ear swelling and proliferation responses compared with wild-type mice. Furthermore, when Ag-pulsed Bid KO migratory cDCs were inoculated into wild-type recipients, an increase in both the rate and percentage of expanded OT-2 T cells expressing IFN-γ was observed. Thus, enhanced Ag presentation function was intrinsic to Bid KO cDCs. Therefore, Bid is an important regulator of LC viability and Ag presentation function.

Dendritic cells (DCs) harbor an active mitochondrion-dependent cell death pathway regulated by Bcl-2 family members and undergo rapid turnover in vivo. However, the functions for mitochondrion-dependent cell death of DCs in immune regulation remain to be elucidated. Here we show that DC-specific knockout of pro-apoptotic Bcl-2 family members, Bax and Bak, induced spontaneous T cell activation and autoimmunity in mice. In addition to a defect in spontaneous cell death, Bax−/−Bak−/− DCs were resistant to killing by CD4+FoxP3+ T regulatory (Treg) cells compared to wild type DCs. Treg cells inhibited the activation of T effector cells by wild type, but not Bax−/−Bak−/− DCs. Bax−/−Bak−/− DCs showed increased propensity for inducing autoantibodies. Moreover, the autoimmune potential of Bax−/−Bak−/− DCs was resistant to suppression by Treg cells. Our data suggest that Bax and Bak not only mediate intrinsic spontaneous cell death in DCs, but also regulate DC killing triggered by Treg cells. Bax- and Bak-dependent cell death mechanisms help to maintain DC homeostasis, and contribute to the regulation of T cell activation and the suppression of autoimmunity.