title: Deletion, but not anergy, is involved in TGF-beta-treated antigen-presenting cell-induced tolerance.
abstract: Intravenous injection of transforming growth factor (TGF-)-beta-treated antigen-presenting cells (APC) pulsed with antigen induces antigen-specific tolerance in both naive and previously primed mice. Although TGF-beta-treated APC-induced tolerance is associated with induction of regulatory T cells and impaired delayed-type hypersensitivity (DTH) responses, the specific mechanisms that mediate this tolerance are not currently known. The goal of the present report was to study the mechanisms involved in TGF-beta-treated APC-induced tolerance by determining the fate of the antigen-specific effector T cells that are regulated. Using a well-characterized system that allows tracking of small numbers of TCR transgenic T cells, we have found that antigen-specific T cell expansion, either in vivo or in vitro, is inhibited in mice that have been injected with TGF-beta-treated APC. The failure of antigen-specific effector T cells to expand did not appear to be due to the induction of anergy, since carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled cells divided normally in response to antigen and adjuvant in vivo, and addition of exogenous IL-2 was unable to restore T cell expansion in in vitro assays. Interestingly, the percentage of CFSE-labeled cells was decreased after >7-8 divisions following culture in vitro, which correlated with a significant increase in cell death. Cell death was prevented and the ability to expand in vitro was restored by treatment with anti-Fas ligand (FasL) antibody. In conclusion, tolerance induced by TGF-beta-treated APC appears to be associated with deletion of antigen-specific T cells involving the Fas-FasL pathway.
authors.affiliation: University of Louisville Health Sciences Center, 319 Abraham Flexner Way, Louisville, KY 40202, USA.
authors.forename: Pascale
authors.initials: P
authors.lastname: Alard
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Clark
authors.forename: Michele M
authors.initials: MM
authors.lastname: Kosiewicz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D017637:Clonal Deletion / Q000276:immunology*; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005452:Fluoresceins / Q000032:analysis; D007108:Immune Tolerance / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics; D010529:Peritoneal Cavity / Q000166:cytology; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000235:genetics; D013388:Succinimides / Q000032:analysis; D013864:Thioglycolates / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000945:Antigens, Differentiation, T-Lymphocyte; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005452:Fluoresceins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D013388:Succinimides; D013864:Thioglycolates; D016212:Transforming Growth Factor beta; D010047:Ovalbumin