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2 Domain Signals Rapid Fas-Independent Cell Death: A Direct Pathway for T Cell-Mediated Killing of Target Cells?1
Departments of
*
Pediatric Research and
Pediatrics, The National Hospital, and
Section for Immune Therapy, The Norwegian Radium Hospital, Oslo, Norway
TCR binding to an MHC class I/peptide complex is a central event in
CTL-mediated elimination of target cells. In this study, we demonstrate
that specific activation of the TCR-binding region of the HLA-A2 class
I 
2 domain induces apoptotic cell death. mAbs to
this region rapidly induced apoptosis of HLA-A2-expressing Jurkat E11
cells, as determined by morphologic changes, phosphatidylserine
exposure on the cell surface, and propidium iodide uptake. In contrast,
apoptosis was not induced following culture with mAbs directed to other
regions of the class I molecule. Death signaling by class I molecules
is apparently dependent on coreceptor activation, as apoptosis is also
signaled by HLA-A2 molecules, where the intracytoplasmic residues were
deleted. HLA class I 2-mediated cell death appeared to
proceed independent of the Fas pathway. Compared with apoptotic
signaling by Fas ligation, HLA class I 2-mediated
responses displayed a faster time course and could be observed within
30 min. Furthermore, class I 2-induced cell death did
not involve observable DNA fragmentation. The apoptotic response was
not affected significantly by peptide inhibitors of IL-1ß converting
enzyme (ICE)-like proteases and CPP32. Taken together, activation of
the TCR-binding domain of the class I 2 helix may result
in apoptotic signaling apparently dependent on a novel death pathway.
Thus, target HLA class I molecules may directly signal apoptotic cell
death following proper ligation by the TCR.
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