title: Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage.
abstract: The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3(+) regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3(+) Treg cells in Aire(+/+) mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells.
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Malchow
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Leventhal
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Saki
authors.initials: S
authors.lastname: Nishi
authors.affiliation: Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address: psavage@bsd.uchicago.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Savage
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D017637:Clonal Deletion; D060966:Clonal Selection, Antigen-Mediated; D002999:Clone Cells; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011467:Prostate / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D000096927:AIRE Protein; C498833:Foxp3 protein, mouse