Table of Contents
  Chapter 29 Immunological Tolerance
     IMMUNOREGULATION
       Ronald H. Schwartz, Daniel L. Mueller
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CD8+ Veto Cells

A mechanism for tolerizing naïve CD8+ precytotoxic T cells has been described by Miller (127), which involves negative immunoregulation by previously activated CD8+ cells (T cells or NK cells). In this model system, a population of precultured MHC-incompatible CD8+ T cells was recognized by unprimed allogeneic CD8+ T cells and the former inactivated the latter; hence, the name "veto cells." These cells acted late in culture (after 20 hours), mediated their effects by cell-cell interaction (not secreted products), and did not compete for lysis of target cells in the CTL assay (as they could be eliminated prior to the assay with anti-MHC antibodies and complement without reversing the effect). The TCR specificity of the veto cell did not matter and engagement of its TCR was not required for its veto function. Instead, it was the recognition of cell-surface peptide/MHC class I antigens on the veto cell by the responding CD8+ T-cell that led to the latter’s inactivation. Evidence that the veto phenomenon can also operate in vivo has come largely from the experiments of Fink et al. (128). Injection of splenic CD8+ T cells into mice differing at MHC class I loci resulted in inhibition of a subsequent in vitro CTL response by the recipient’s T cells against donor class I molecules.

A molecular mechanism for vetoing has been described which involves signaling back through the MHC class I molecule following its interaction with CD8 on the veto cell (129). CD8 negative variants of clones otherwise capable of vetoing were found to lose their ability to veto. Furthermore, cell lines expressing the correct peptide/MHC complex, but which were not veto cells, became veto cells when transfected with a CD8 gene. Finally, a veto effect could be activated with peptide/MHC positive, CD8 negative cells by adding a monoclonal antibody against the a3 domain of the MHC class I molecule (the molecular region for CD8 binding). Conversely, a CD8+ veto cell could be prevented from killing by a monoclonal antibody against CD8, which blocked its interaction with the MHC molecule. These results suggest that the veto signal is initiated by the interaction of CD8 on the veto cell with the a3 domain of an MHC class I molecule on the target cell, but only when the latter cell simultaneously becomes activated through its TCR via recognition of a peptide/MHC molecule on the veto cell. The effect of this dual signaling by veto cells is to make the responding T cells susceptible to Fas/FasL-mediated apoptosis. The function of this mechanism in self-tolerance is not clear, but it may play a role in eliminating autoreactive CD8+ T cells specific for blast antigens expressed on activated CTLs. In a clinical setting, CD8+ veto cells raised against irrelevant third-party targets have been used by Reisner and colleagues to prevent graft rejection in allogeneic bone marrow transplantation using large doses of CD34+ stem cells under minimal conditioning regimens.


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