title: Novel mechanisms underlying the immediate and transient global tolerization of splenic dendritic cells after vaccination with a self-antigen.
abstract: Dendritic cells (DCs) are important orchestrators of the immune response, ensuring that immunity against pathogens is generated, whereas immunity against healthy tissues is prevented. Using the tumor Ag MUC1, we previously showed that i.v. immunization of MUC1 transgenic mice, but not wild-type, with a MUC1 peptide resulted in transient tolerization of all splenic DCs. These DCs did not upregulate costimulatory molecules and induced regulatory T cells rather than effector T cells. They were characterized by suppressed expression of a cohort of pancreatic enzymes not previously reported in DCs, which were upregulated in DCs presenting the same MUC1 peptide as a foreign Ag. In this article, we examined the self-antigen-tolerized DC phenotype, function, and mechanisms responsible for inducing or maintaining their tolerized state. Tolerized DCs share some characteristics with immature DCs, such as a less inflammatory cytokine/chemokine profile, deficient activation of NF-κB, and sustained expression of zDC and CCR2. However, tolerized DCs demonstrated a novel inducible expression of aldehyde dehydrogenase 1/2 and phospho-STAT3. Suppressed expression of one of the pancreatic enzymes, trypsin, in these DC impeded their ability to degrade extracellular matrix, thus affecting their motility. Suppressed metallopeptidases, reflected in low expression of carboxypeptidase B1, prevented optimal Ag-specific CD4(+) T cell proliferation suggesting their role in Ag processing. Tolerized DCs were not refractory to maturation after stimulation with a TLR3 agonist, demonstrating that this tolerized state is not terminally differentiated and that tolerized DCs can recover their ability to induce immunity to foreign Ags.
authors: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors: Adam M
authors: AM
authors: Farkas
authors: Olivera J
authors: OJ
authors: Finn
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000276:immunology; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D043424:Carboxypeptidase B / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D045726:Metalloproteases / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010179:Pancreas / Q000276:immunology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D013154:Spleen / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014611:Vaccination / Q000379:methods
chemical_list: D001324:Autoantigens; C515335:Ccr2 protein, mouse; D018925:Chemokines; D016328:NF-kappa B; D054390:Receptors, CCR2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D000444:Aldehyde Dehydrogenase; D045726:Metalloproteases; D043424:Carboxypeptidase B