Activation of caspase-3-like enzymes in non-apoptotic T cells

Abstract

The activation of the caspase family of cysteine proteases is a key step in the implementation of apoptotic cell death leading to further downstream effects such as DNA fragmentation. In cultured tumor cells, caspase activity appears only when cells are undergoing apoptosis. Here we show that human and murine T lymphocytes acquire high intracellular activities of cell death-specific caspases upon activation by mitogens and IL-2 without evidence that apoptosis is proceeding. The highest activity is seen when cells are mitogen activated for 3 days. On a per cell basis, caspase activity in activated T cells is much higher than in tumor cells induced to undergo apoptosis. In the presence of exogenously added IL-2 cells stay alive and maintain a high level of caspase activity while IL-2 withdrawal results in cell death and decline of caspase activity. Caspase activity can also be measured in extracts from spleen and lymph nodes from mice injected with superantigen. While in tumor cell lines caspase activity correlates with cleavage of poly(ADP)-ribose polymerase (PARP) and DNA fragmentation, in activated T cells cleavage products of cellular PARP can be detected whereas DNA fragmenting activity appears only upon IL-2 withdrawal which coincides with cell death. These data show that caspase activation in intact cells does not necessarily lead to cell death and argue for a checkpoint in the apoptotic pathway downstream of caspases. Furthermore, they provide a molecular correlate for the high susceptibility of activated T cells for apoptosis.

Defective caspase-3 relocalization in non-small cell lung carcinoma

“…There are now several examples of caspase activation without cell death. Thus, activation of caspase-3 like enzymes was reported in non-apoptotic T lymphocytes (Miossec et al, 1997;Wilhelm et al, 1998). The authors provided evidence for caspase-mediated cleavage of PARP in the absence of DNA fragmentation and apoptosis.…”

Caspases and nitric oxide broadly regulate dendritic cell maturation and surface expression of class II MHC proteins

“…Notably however, mammalian caspases have also evolved additional roles in inflammatory response (33). More recently, roles of caspases in T cell activation or, more broadly, activation of T, B and NK cells, erythroid differentiation, and some aspects of cardiac function have been demonstrated (34)(35)(36)(37)(38)(39)(40)(41). Additionally, a caspase-mediated endoproteolysis of the NF-B factor Relish has an important role in the innate immune response in Drosophila (42).…”

IL-7-Regulated Homeostatic Maintenance of Recent Thymic Emigrants in Association with Caspase-Mediated Cell Proliferation and Apoptotic Cell Death

“…There is growing evidence for the participation of caspases and other apoptosis regulators not only in cell death, but also in the control of other cell processes. Earliest reports of these alternative roles for caspases came from studies identifying caspase-3 processing in nonapoptotic PBMCs after polyclonal activation (15,16). Further support came from studies of FADD, a protein associated with upstream events in caspase activation.…”

“…Recently, the emergence of a role for caspases in cell cycling has also been proposed (15,16). It has been shown that in mature T cells, upon early TCR stimulation, caspase activity can be detected in nonapoptotic cells, and this activation is required for T cell proliferation (17,18).…”