Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-05, Vol.44 (5), p.1102-1113
• Main Authors: Malchow, Sven, Leventhal, Daniel S., Lee, Victoria, Nishi, Saki, Socci, Nicholas D., Savage, Peter A.
• Format: Article
• Language: English
• Subjects: AIRE Protein; Animals; Antigens; Autoantigens - immunology; Autoimmunity - genetics; Cancer; Cell Differentiation; Cell Lineage; Clonal Deletion; Clonal Selection, Antigen-Mediated; Clone Cells; Data analysis; Experiments; Flow cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Immune Tolerance - genetics; Lymphocytes; Male; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Prostate - immunology; Proteins; Scholarships & fellowships; Software; Statistical analysis; T cell receptors; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets - physiology; T-Lymphocytes, Regulatory - physiology; Thymus Gland - immunology; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.02.009

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. [Display omitted] •Aire impacts the peripheral repertoire of both Treg cells and Tconv cells•The autoimmune defect in Aire−/− mice maps to the Tconv cell compartment•Treg-biased clones are diverted into the Tconv cell subset in Aire−/− mice•Diverted clones dominate the Tconv cell infiltrate in prostatic lesions Aire-dependent promiscuous gene expression in the thymus is critical for the protection of peripheral organs from autoimmune attack. Savage and colleagues demonstrate that in Aire−/− mice, Treg cell-biased clones are mis-directed into the T conventional cell subset and dominate the T cell infiltrate in autoimmune target lesions.