Ikaros is a principal regulator of Aire mTEC homeostasis, thymic mimetic cell diversity, and central tolerance.
Fiche publication
Date publication
octobre 2023
Journal
Science immunology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CHAN Susan, Dr KASTNER Philippe
Tous les auteurs :
Sin JH, Sucharov J, Kashyap S, Wang Y, Proekt I, Liu X, Parent AV, Gupta A, Kastner P, Chan S, Gardner JM, Ntranos V, Miller CN, Anderson MS, Schjerven H, Waterfield MR
Lien Pubmed
Résumé
Mutations in the gene encoding the zinc-finger transcription factor Ikaros () are found in patients with immunodeficiency, leukemia, and autoimmunity. Although Ikaros has a well-established function in modulating gene expression programs important for hematopoietic development, its role in other cell types is less well defined. Here, we uncover functions for Ikaros in thymic epithelial lineage development in mice and show that expression in medullary thymic epithelial cells (mTECs) is required for both autoimmune regulator-positive (Aire) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of in mice results in a profound decrease in Aire mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity, and its deletion results in a marked expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with mutations.
Mots clés
Humans, Mice, Animals, Central Tolerance, Cell Differentiation, Thymus Gland, Transcription Factors, Gene Expression Regulation
Référence
Sci Immunol. 2023 10 27;8(88):eabq3109