Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase-induced c-Jun NH2-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis

doi:10.1083/jcb.139.6.1523

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© The Rockefeller University Press, 0021-9525/1997//1523 $5.00
The Journal of Cell Biology, Volume 139, Number 6, , 1997 1523-1531

Article

Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase–induced c-Jun NH₂-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis

Søren Skov, Pia Klausen, and Mogens H. Claesson

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 arrestand apoptosis. The aim of the current study was to investigatethe intracellular signal pathways that mediate these effects.

MHC-I ligation of human Jurkat T cells induced a morphologicallydistinct form of apoptosis within 6 h. A specific caspase inhibitor,which inhibited Fas-induced apoptosis, did not affect apoptosisinduced by MHC-I ligation. Furthermore, MHC-I–inducedapoptosis did not involve cleavage and activation of the poly(ADP-ribose) polymerase (PARP) endonuclease or degradation of genomicDNA into the typical fragmentation ladder, both prominent eventsof Fas-induced apoptosis. These results suggest that MHC-I ligationof 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-3kinase (PI-3) kinase was tyrosine phosphorylated after ligationof MHC-I and the PI-3 kinase inhibitor wortmannin selectivelyblocked MHC-I–, but not Fas-induced, apoptosis. As thec-Jun NH₂-terminal kinase (JNK) can be activated by PI-3 kinaseactivity, and has been shown to be involved in apoptosis oflymphocytes, we examined JNK activation after MHC-I ligation.Strong JNK activity was observed after MHC-I ligation and theactivity was completely blocked by wortmannin. Inhibition ofJNK activity, by transfecting cells with a dominant-negativeJNKK– MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation. These results suggest a critical engagementof PI-3 kinase–induced JNK activity in apoptosis inducedby MHC-I ligation.

Abbreviations used in this paper: 7-AAD, 7-aminoactinomycin D; Ab, antibody; ATA, aurintricarboxylic acid; CTL, cytotoxic T lymphocyte; ERK, extracellular signal-regulated kinase; ICE, interleukin-1β–convertase enzyme; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MHC-I, major histocompatibility complex class I; PARP, poly(ADP-ribose) polymerase; PI-3, phosphoinositide-3 kinase; TCR–CD3, T cell antigen receptor complex.

Address all correspondence to Søren Skov, Laboratoryof Experimental Immunology, Department of Medical Anatomy,The Panum Institute, University of Copenhagen, Blegdamsvej3, Building 18.3, 2200 Copenhagen N, Denmark. Fax: 45.35.32.72.69.E-mail: s.skov{at}mai.ku.dk

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