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Laboratory of Experimental Immunology, Department of Medical Anatomy, The Panum Institute, University of Copenhagen,
2200 Copenhagen, Denmark
Ligation of major histocompatability complex class I (MHC-I) molecules expressed on T cells
leads to both growth arrest and apoptosis. The aim of
the current study was to investigate the intracellular
signal pathways that mediate these effects.
MHC-I ligation of human Jurkat T cells induced a
morphologically distinct form of apoptosis within 6 h. A
specific caspase inhibitor, which inhibited Fas-induced
apoptosis, did not affect apoptosis induced by MHC-I
ligation. Furthermore, MHC-I-induced apoptosis did
not involve cleavage and activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation of genomic DNA into the typical fragmentation
ladder, both prominent events of Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T cells induce apoptosis through a signal pathway
distinct from the Fas molecule.
In our search for other signal pathways leading to
apoptosis, we found that the regulatory 85-kD subunit
of the phosphoinositide-3 kinase (PI-3) kinase was tyrosine phosphorylated after ligation of MHC-I and the
PI-3 kinase inhibitor wortmannin selectively blocked
MHC-I-, but not Fas-induced, apoptosis. As the c-Jun
NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has been shown to be involved in
apoptosis of lymphocytes, we examined JNK activation
after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and the activity was completely
blocked by wortmannin. Inhibition of JNK activity, by
transfecting cells with a dominant-negative JNKK-
MKK4 construct, led to a strong reduction of apoptosis
after MHC-I ligation. These results suggest a critical
engagement of PI-3 kinase-induced JNK activity in
apoptosis induced by MHC-I ligation.
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