title: Peripheral tolerance to a nuclear autoantigen: dendritic cells expressing a nuclear autoantigen lead to persistent anergic state of CD4+ autoreactive T cells after proliferation.
abstract: It remains unknown why the T cell tolerance to nuclear autoantigens is impaired in systemic autoimmune diseases. To clarify this, we generated transgenic mice expressing OVA mainly in the nuclei (Ld-nOVA mice). When CD4+ T cells from DO11.10 mice expressing a TCR specific for OVA(323-339) were transferred into Ld-nOVA mice, they were rendered anergic, but persisted in vivo for at least 3 mo. These cells expressed CD44(high), CD45RB(low), and were generated after multiple cell divisions, suggesting that anergy is not the result of insufficient proliferative stimuli. Whereas dendritic cells (DCs) from Ld-nOVA (DCs derived from transgenic mice (TgDCs)), which present rather low amount of the self-peptide, efficiently induced proliferation of DO11.10 T cells, divided T cells stimulated in vivo by TgDCs exhibited a lower memory response than T cells stimulated in vitro by peptide-pulsed DCs. Furthermore, we found that repeated transfer of either TgDCs or DCs derived from wild-type mice pulsed with a lower concentration of OVA(323-339) induced a lower response of DO11.10 T cells in Ag-free wild-type recipients than DCs derived from wild-type mice. These results suggest that peripheral tolerance to a nuclear autoantigen is achieved by continuous presentation of the self-peptide by DCs, and that the low expression level of the peptide might also be involved in the induction of hyporesponsiveness.
authors.affiliation: Department of Allergy and Rheumatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.forename: Yoshikata
authors.initials: Y
authors.lastname: Misaki
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsunekawa
authors.forename: Keigo
authors.initials: K
authors.lastname: Setoguchi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000096:biosynthesis* / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D007117:Immunization, Secondary; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D010446:Peptide Fragments / Q000096:biosynthesis; D010455:Peptides / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D009687:Nuclear Proteins; C111390:OVA 323-339; D010446:Peptide Fragments; D010455:Peptides; D010047:Ovalbumin