title: Generation of anergic and regulatory T cells following prolonged exposure to a harmless antigen.
abstract: Regulatory CD4(+) T cells are known to develop during the induction of donor-specific peripheral tolerance to transplanted tissues; it is proposed that such tolerance is a consequence of persistent, danger-free stimulation by Ag. To test this hypothesis, male RAG-1(-/-) mice were recolonized with small numbers of monospecific CD4(+) T cells specific for the male H-2E(k)-restricted Ag Dby. After 6 wk in the male environment, the monospecific CD4(+) T cells, having recolonized the host, had become anergic to stimulation in vitro and had acquired a regulatory capacity. CD4(+) T cells in these mice expressed higher levels of CTLA-4 and glucocorticoid-induced TNF-related receptor than naive CD4(+) T cells, but only 3% of the recolonizing cells were CD25(+) and did not express significant foxP3 mRNA. In vivo, these tolerant T cells could censor accumulation of, and IFN-gamma production by, naive T cells, with only a slight inhibition of proliferation. This suppressive effect was not reversed by the addition of fresh bone marrow-derived male dendritic cells. These results suggest that persistent exposure to Ag in conditions that fail to evoke proinflammatory stimuli leads to the development of T cells that are both anergic and regulatory.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fairchild
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D018920:Coculture Techniques; D053487:DEAD-box RNA Helicases; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D016130:Immunophenotyping; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011506:Proteins / Q000008:administration & dosage* / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*
chemical_list: D000941:Antigens; D018398:Homeodomain Proteins; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D012333:RNA, Messenger; C064658:RAG-1 protein; C115600:Ddx3y protein, mouse; D053487:DEAD-box RNA Helicases