title: The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.
abstract: We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow-derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8alpha(+) dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced beta-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c(+)CD8alpha(+) cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8alpha(+) DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.
authors.affiliation: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia. belz@wehi.edu.au
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Georg M N
authors.initials: GM
authors.lastname: Behrens
authors.forename: Chris M
authors.initials: CM
authors.lastname: Smith
authors.forename: Jacques F A P
authors.initials: JF
authors.lastname: Miller
authors.forename: Claerwen
authors.initials: C
authors.lastname: Jones
authors.forename: Kristina
authors.initials: K
authors.lastname: Lejon
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
authors.forename: Scott N
authors.initials: SN
authors.lastname: Mueller
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D007108:Immune Tolerance; D016130:Immunophenotyping; D007328:Insulin / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats
chemical_list: D015703:Antigens, CD; D001426:Bacterial Proteins; D017931:DNA Primers; D007328:Insulin; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria