title: Distinct mechanisms mediate naive and memory CD8 T-cell tolerance.
abstract: Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030-1319, USA.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Jellison
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Turner
authors.forename: David A
authors.initials: DA
authors.lastname: Blair
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Lingenheld
authors.forename: Li
authors.initials: L
authors.lastname: Zu
authors.forename: Lynn
authors.initials: L
authors.lastname: Puddington
authors.forename: Leo
authors.initials: L
authors.lastname: Lefrançois
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D001324:Autoantigens; D016827:CD8 Antigens