Mechanisms of tolerance induced by transforming growth factor-beta-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.
Transforming growth factor (TGF)-beta-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-beta-treated APC. Interestingly, TGF-beta-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-beta-treated APC-induced CD8 regulatory T cells did not suppress effector T cell function in vivo through the production of IL-4, TGF-beta 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-beta-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-beta-treated APC. In conclusion, our data indicate that TGF-beta-treated APC effect tolerance in primed mice via a Fas-FasL-mediated mechanism that requires CD8 cells.
Kosiewicz
Michele M
MM
Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40202, USA. mmkosi01@gwise.louisville.edu
Alard
Pascale
P
Liang
Shuang
S
Clark
Sherry L
SL
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007114:Immunization; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D010047:Ovalbumin