No abstract

Increasing evidence has shown that death signaling in T cells is regulated in a complicated way. Molecules other than death receptors can also trigger T-cell death. Here, we demonstrate for the first time that P-selectin glycoprotein ligand-1 (PSGL-1) or CD162 molecules crosslinked by an anti-PSGL-1 monoclonal antibody, TAB4, can trigger a death signal in activated T cells. In contrast to classic cell death, PSGL-1-mediated T-cell death is caspase independent. It involves translocation of apoptosis-inducing factor from mitochondria to nucleus and mitochondrial cytochrome c release. Ultrastructurally, both peripheral condensation of chromatin and apoptotic body were observed in PSGL-1-mediated T-cell death. Collectively, this study demonstrates a novel role for PSGL-1 in controlling activated T-cell death and, thus, advances our understanding of immune regulation. IntroductionDeath of T cells is fundamental in proper immune responses. In central and peripheral lymphoid organs, T-cell death occurs as a regulated event to ensure self-tolerance. [1][2][3][4] As the consequence of an immune response in normal conditions, most antigen-activated T cells die subsequently. [5][6][7] Activated T-cell death plays an important role in shaping and maintaining the T-cell repertoire and in avoiding undesired immune responses. Therefore, clarification of molecular mechanisms that determine death of activated T cells becomes imperative.According to current understanding, activated T-cell death occurs in at least 2 conditions: cytokine withdrawal and repeated antigenic stimulation. 8 In the former, when there is no further antigen stimulation, both interleukin 2 (IL-2) production and IL-2 receptor expression decline, and the death because of cytokine withdrawal ensues. 9,10 The latter is antigen driven and mediated through death receptors such as Fas and tumor necrosis factor (TNF) receptor. [11][12][13] Both conditions of activated T-cell death occur by way of activation of caspases and are strictly dependent on caspase-3. 14,15 Such classic caspase-activating death pathways may culminate mitochondrial dysfunction and cytochrome c release. 16 There is now increasing evidence for the existence of alternative, caspase-independent machinery of cell death in T-cell development and activation. [17][18][19][20][21][22][23] Fas-deficient lpr mice are able to eliminate T cells. 24 Additionally, by repeated antigenic stimulation, activated T-cell death in FLIP (FLICE [FADD (Fas receptor-associated death domain)-like IL-1␤-converting enzyme]-inhibitory protein) transgenic mice does occur. These mice do not develop lymphoproliferative disease despite their resistance to Fas-triggered death. 25 In line with these observations, several reports have shown that caspase inhibition fails to prevent cell death on some death stimuli, 17,18,26 suggesting the involvement of other alternative mechanisms. However, these caspase-independent pathways may be triggered in activated T cells when subjected to some death stimuli other than death receptors. ...

Various sedative agents, including dexmedetomidine (dex), induce immunosuppression, and enhance infection progression. However, there was no information on how anesthetic affects local and systemic cellular immune function. We conducted this study to examine the impact of dex on the differentiation and function of immune cells at site of inflammation and in peripheral blood during endotoxemia of mice. In BALB/c mice with and without endotoxemia, we evaluated the influence of two dosages of 5 and 50 mcg/kg/h intravenous dex on immune cells: including number of T cells (CD3), B cells (CD19), natural killer cells (CD8a), monocytes (CD11b), and macrophages (Mac-3) in peripheral blood, the activities of macrophages in peripheral blood and in peritoneal lavage, and proliferation of B and T cells and of natural killer cells activity in the spleen. Endotoxemia increased the number of CD3 T cells, CD 19 B cells and macrophages in the peripheral blood, augmented macrophage activity in the peritoneum, and increased T cell proliferation and natural killer cell activity in the spleen. Further administration of 5 mcg/kg/h dex attenuated systemic increase in number of T cells, B cells, and macrophages during endotoxemia and 50 mcg/kg/h dex significantly attenuated the increase in activity of macrophages in the peripheral blood during endotoxemia. In the peritoneum, however, 5 mcg/kg/h dex preserved and 50 mcg/kg/h dexmedetomidine enhanced the activity of macrophages during endotoxemia. Increased in proliferation of T cells in spleen during endotoxemia was attenuated by both doses of dex. Last, 50 mcg/kg/h dex enhanced natural killer cells activity during endotoxemia. While preserving the effects of endotoxemia on macrophage's activity in the infection site and natural killer cell's activity in the spleen, dex decreased systemic fulminant immune reaction in endotoxemia, by attenuating the augmented response in the number of T cells, B cells and macrophages, activity of macrophages in the peripheral blood, and proliferation of T cells in spleen during endotoxemia.