OX40 is a recently identified T-cell co IntroductionT cells with regulatory properties are critical to the induction of self-tolerance and acquired tolerance. 1,2 Among the cell types that exhibit potent suppressor functions, the CD4 ϩ Foxp3 ϩ regulatory T cells (Tregs) are particularly important, as deficiency or functional impairment of this cell type often leads to the development of autoimmunity and the failure to establish acquired tolerance, 3,4 albeit other regulatory cell types also contribute to tolerance via different mechanisms. 5 The CD4 ϩ Foxp3 ϩ Tregs are not a uniform cell type. Depending on the origin of these cells, the CD4 ϩ Foxp3 ϩ T cells can be divided into those that are developed in the thymus (natural Tregs) and those that are induced in the periphery (induced Tregs). 6 Natural Foxp3 ϩ Tregs are selected and matured in the thymus, and then exported to the periphery where they suppress potentially cytopathic T cells. 7 It is well known that lineage commitment of the natural Foxp3 ϩ Tregs requires Foxp3, 8,9 and their survival and expansion demand the presence of IL-2 and expression of IL-2 receptors. 10 However, some activated T effector cells can be converted to Foxp3 ϩ Tregs in the periphery and such induced Foxp3 ϩ Tregs also act as potent suppressor cells. 11,12 From a therapeutic point of view, therapies that can preserve or expand the Foxp3 ϩ Tregs and at the same time inhibit cytopathic T effector cells would be highly desirable in the induction of transplant tolerance or in the treatment of autoimmune diseases.Phenotypically, Foxp3 ϩ Tregs and activated T effector cells often express similar cell surface molecules. For example, both cell types express CD25, CD28, CD154, GITR, CTLA-4, and others, although the functions of such molecules are not always the same in both cell types. 4 Recently, it has been shown that the CD4 ϩ CD25 ϩ Tregs constitutively express OX40 (also called CD134), 13 a new costimulatory molecule that belongs to the TNF-R superfamily. 14 Also, T effector cells, though they do not express OX40 at resting state, can readily express OX40 upon activation, 13 and OX40 engagement delivers a potent costimulatory signal to T effector cells. 15 The recent finding that deliberately stimulating OX40 in vivo can break tolerance to peptide antigens 16 and that blocking OX40 costimulation can enable allograft survival in stringent transplant models 17 suggests that the impact of OX40 signaling on a regulatory type of immune response is likely to be profound. However, very little is known about the role of OX40 in regulating the Foxp3 ϩ Tregs. There are 2 reports in the literature suggesting that OX40 may be capable of modifying the suppressor functions of Tregs, but the findings appear to be contradictory. 18,19 As OX40, like CD25, can be expressed by both Foxp3 ϩ Tregs and activated T effector cells, partition of such functionally distinct T-cell subsets in the initial studies based solely on the CD25 marker has obvious limitations. Moreover, activated T effector cells, which...

Higher rate of glycolysis has been long observed in cancer cells, as a vital enzyme in glycolysis, lactate dehydrogenase A (LDH-A) has been shown with great potential as an anti-cancer target. Accumulating evidence indicates that inhibition of LDH-A induces apoptosis mediated by oxidative stress in cancer cells. To date, it's still unclear that whether autophagy can be induced by LDH-A inhibition. Here, we investigated the effects of oxamate, one classic inhibitor of LDH-A in non-small cell lung cancer (NSCLC) cells as well as normal lung epithelial cells. The results showed that oxamate significantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. As previous studies reported, LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest in H1395 cells. However, when being exposed to oxamate, A549 cells underwent autophagy as a protective mechanism against apoptosis. Furthermore, we found evidence that LDH-A inhibition induced G0/G1 arrest dependent on the activation of GSK-3β in A549 cells. Taken together, our results provide useful clues for targeting LDH-A in NSCLC treatment and shed light on the discovery of molecular predictors for the sensitivity of LDH-A inhibitors.

No abstract

No abstract