Caspase inhibition blocks human T cell proliferation by suppressing appropriate regulation of IL-2, CD25, and cell cycle-associated proteins.
Caspases have been described as proteases essential for the release of certain cytokines and for initiation as well as execution of apoptosis. Increasing evidence indicates, however, that caspase activity is also required for activation-induced proliferation of mature T lymphocytes. The molecular mechanism, how caspase activity facilitates T cell proliferation, is still controversially discussed. In this study, we show that proliferation of human T cells in response to a specific antigenic stimulus is completely prevented by caspase inhibition. In addition, we demonstrate that this lack of proliferation is due to a failure to initiate cell cycle progression, but not the result of increased T cell death. Our results demonstrate that caspase inhibition leads to strongly reduced IL-2 release, failure to up-regulate CD25, and a lack of proper regulation of cell cycle-associated proteins. Furthermore, T cell proliferation was partially rescued by addition of exogenous IL-2. Using Jurkat cells, we show that in the absence of caspase-8, the mitogen-induced activation of the transcription factor NF-kappaB is moderately diminished, while the activity of the composite element CD28 response element and NF-IL-2B AP-1 sites is strongly reduced. Finally, we provide evidence that caspase inhibition suppresses the activation of purified monocytes by bacterial Ags.
Falk
Markus
M
Institut für Immunologie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Germany.
Ussat
Sandra
S
Reiling
Norbert
N
Wesch
Daniela
D
Kabelitz
Dieter
D
Adam-Klages
Sabine
S
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000032:analysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007376:Interleukin-2; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases