Susceptibility to cell death is a dominant phenotype: triggering of activation-driven T-cell death independent of the T-cell antigen receptor complex.

Abstract

The failure of Thy-1 and Ly-6 to trigger interleukin-2 production in the absence of surface T-cell antigen receptor complex (TCR) expression has been interpreted to suggest that functional signalling via these phosphatidylinositol-linked alternative activation molecules is dependent on the TCR. We find, in contrast, that stimulation of T cells via Thy-1 or Ly-6 in the absence of TCR expression does trigger a biological response, the cell suicide process of activation-driven cell death. Activation-driven cell death is a process of physiological cell death that likely represents the mechanism of negative selection of T cells. The absence of the TCR further reveals that signalling leading to activation-driven cell death and to lymphokine production are distinct and dissociable. In turn, the ability of alternative activation molecules to function in the absence of the TCR raises another issue: why immature T cells, thymomas, and hybrids fail to undergo activation-driven cell death in response to stimulation via Thy-1 and Ly-6. One possibility is that these activation molecules on immature T cells are defective. Alternatively, susceptibility to activation-driven cell death may be developmentally regulated by TCR-independent factors. We have explored these possibilities with somatic cell hybrids between mature and immature T cells, in which Thy-1 and Ly-6 are contributed exclusively by the immature partner. The hybrid cells exhibit sensitivity to activation-driven cell death triggered via Thy-1 and Ly-6. Thus, the Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 triggering, the mature phenotype of sensitivity to cell death is genetically dominant.

The cytoplasmic tail of the T cell receptor ζ chain is dispensable for antigen‐mediated T cell activation

“…However, functional differences have already been documented between T cell hybridoma and the BW5147 parental cells. For instance, BW5147 fails to undergo activation-driven cell death in response to stimulation viaThy-1 or Ly-6 whereasT cell hybridomas resulting from the fusion of BW5147 and of a matureTcel1 do [32]. In the latter instance the parental mature Tcells may have provided factor(s) that confer susceptibility to activationdriven cell death.…”

Thy-1 Antigen Mediates Apoptosis of Rat Glomerular Cells in vitro and in vivo

“…Apart from an inhibition experiment in comple ment-deprived rats [4], it was shown that nephritis could be worsened in rats treated with antibodies against mem brane inhibitors of complement [S. Matsuo et al, pers. commun], Anti-Thy-1 mAb has been found to induce activation-driven cell death in transformed T cell hybridoma and non-transformed T cell lines [22,23], as well as apoptosis in Thy-l-positive thymocytes [13], Thus, both forms of cell death may coexist in the initial injury. Fur ther investigation is necessary to clarify the roles of each form of cell death in this model.…”

Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism.

“…Previous studies have shown that mAb directed at GPIanchored molecules, such as Thy-1 and Ly-6, are capable of activating mature T cells to proliferate in a manner similar to antigen-or anti-TCIL/CD3 mAb-driven T cell activation (33). The same stimuli have also been found to elicit T hybridoma or nontransformed T cell death (47,48). This ADCD is of apoptotic nature and can be prevented by RNA and protein synthesis inhibitors, and the two compounds EGTA and cyclosporin A (47)(48)(49).…”