The TCR-Binding Region of the HLA Class I α2 Domain Signals Rapid Fas-Independent Cell Death: A Direct Pathway for T Cell-Mediated Killing of Target Cells?

Abstract

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 α2 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 α2-mediated cell death appeared to proceed independent of the Fas pathway. Compared with apoptotic signaling by Fas ligation, HLA class I α2-mediated responses displayed a faster time course and could be observed within 30 min. Furthermore, class I α2-induced cell death did not involve observable DNA fragmentation. The apoptotic response was not affected significantly by peptide inhibitors of IL-1β converting enzyme (ICE)-like proteases and CPP32. Taken together, activation of the TCR-binding domain of the class I α2 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.

CD99 at the crossroads of physiology and pathology

“…C D 9 9 e n g a g e m e n t i n d u c e s phosphatidylserine exposure on the surface of the immature thymocytes (Aussel et al 1993;Choi et al 1998), but cell death proceeds through classical or non-classical apoptotic pathways depending on the different CD99 domains that are activated by distinctive antibodies (Aussel et al 1993;Pettersen et al 2001). The reason behind why different CD99 domains are linked to different death pathways is not clear, but a similar complex situation in which the engagment of distinct domains induces either caspase-dependent or caspase-independent cell death has either been reported with other molecules such as the major histocompatibility complex (MHC) class I molecules (Genestier et al 1998;Pettersen et al 1998). Of note, CD99 participates to the upregulation of MHC class I and II and TCR expression on the thymocytes (Choi et al 1998;Sohn et al 2001).…”

Induction of MHC Class I Expression on Immature Thymocytes in HIV-1-Infected SCID-hu Thy/Liv Mice: Evidence of Indirect Mechanisms

“…MHCI on DP thymocytes may interact with CD8/TCR to interfere with the proper selection signals required for thymocyte maturation and survival. In addition, MHCI itself or in combination with other receptors may transduce signals affecting cell survival (59,60). Further studies of HIV-1 pathogenesis in the SCID-hu Thy/Liv mouse and in the HF-TOC model will not only help understand the mechanisms of HIV-1-induced thymus destruction, but will also shed light on the mechanisms of thymocyte selection and maturation.…”