title: Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection.
abstract: Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8(+) T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity.
authors.affiliation: Swiss Vaccine Research Institute and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Enouz
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrié
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bevan
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zehn
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D060966:Clonal Selection, Antigen-Mediated / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007156:Immunologic Memory; D007239:Infections / Q000276:immunology* / Q000821:virology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology / Q000821:virology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
chemical_list: D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell