THE TCR-BINDING REGION OF THE HLA-CLASS-I-ALPHA(2) DOMAIN SIGNALS RAPID FAS-INDEPENDENT CELL-DEATH - A DIRECT PATHWAY FOR T-CELL-MEDIATED KILLING OF TARGET-CELLS

TCR binding to an MHC class I/peptide complex is a central event in CT L-mediated elimination of target cells, In this study, we demonstrate that specific activation of the TCR-binding region of the HLA-AZ class I alpha(2) domain induces apoptotic cell death. mAbs to this region r apidly induced apoptosis of HLA-A2-expressing Jurkat E11 cells, as det ermined by morphologic changes, phosphatidylserine exposure on the cel l 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 d ependent on coreceptor activation, as apoptosis is also signaled by HL A-A2 molecules, where the intracytoplasmic residues were deleted, HLA class I alpha(2)-mediated cell death appeared to proceed independent o f the Fas pathway. Compared with apoptotic signaling by Pas ligation, HLA class I alpha(2)-mediated responses displayed a faster time course and could be observed within 30 min. Furthermore, class I alpha(2)-in duced cell death did not involve observable DNA fragmentation. The apo ptotic response was not affected significantly by peptide inhibitors o f IL-1 beta converting enzyme (ICE)-like proteases and CPP32, Taken to gether, activation of the TCR-binding domain of the class I alpha(2) h elix 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.