International Immunology Advance Access originally published online on March 29, 2004
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International Immunology, Vol. 16, No. 5, pp. 697-706,
May 2004
© 2004 Japanese Society for Immunology
Mechanisms of tolerance induced by transforming growth factor-ß-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
1 Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Correspondence to: M. M. Kosiewicz; E-mail: mmkosi01{at}gwise.louisville.edu
Transmitting editor: W. Strober
Transforming growth factor (TGF)-ß-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-ß-treated APC. Interestingly, TGF-ß-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-ß-treated APC-induced CD8 regulatory T cells did not suppress effector T cell function in vivo through the production of IL-4, TGF-ß 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-ß-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-ß-treated APC. In conclusion, our data indicate that TGF-ß-treated APC effect tolerance in primed mice via a Fas–FasL-mediated mechanism that requires CD8 cells.
Keywords: delayed-type hypersensitivity, deletion, Fas
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