Mechanisms of tolerance induced by transforming growth factor- -treated antigen-presenting cells: CD8 regulatory T cells inhibit the effector phase of the immune response in primed mice through a mechanism involving Fas ligand

Abstract

Transforming growth factor (TGF)‐β‐treated antigen‐presenting cells [(APC) adherent peritoneal exudate cells] induce a profound tolerance in primed mice that is thought to be mediated by regulatory T cells induced in the spleen. In the current study, we investigated the mechanism(s) involved in tolerance induced in primed mice by TGF‐β‐treated APC. Interestingly, TGF‐β‐treated APC from class II knockout mice were unable to mediate tolerance in primed mice and failed to induce not only CD4, but also CD8 regulatory T cells. However, the results of several experiments indicated that it was the CD8 regulatory T cells that were required for tolerance induced in primed mice. Using neutralizing antibody, we found that TGF‐β‐treated APC‐induced CD8 regulatory T cells did not suppress effector T cell function in vivo through the production of IL‐4, TGF‐β or IL‐10. On the other hand, our data showed that the Fas–Fas ligand (FasL) pathway was involved in this form of tolerance since TGF‐β‐treated APC could not mediate tolerance in primed FasL‐deficient mice and CD8 T cells from FasL‐deficient mice were unable to suppress effector T cell responses. Moreover, the targets of FasL‐mediated suppression were found to be the effector T cells as suggested by the data showing that Fas‐deficient effector T cells were not susceptible to suppression mediated by CD8 regulatory T cells induced by TGF‐β‐treated APC. In conclusion, our data indicate that TGF‐β‐treated APC effect tolerance in primed mice via a Fas–FasL‐mediated mechanism that requires CD8 cells.