Ikaros is a principal regulator of Aire + mTEC homeostasis, thymic mimetic cell diversity, and central tolerance.

Autor:	Sin JH; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Sucharov J; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA., Kashyap S; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Wang Y; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; 10x Genomics, Pleasanton, CA, USA., Proekt I; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Liu X; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Parent AV; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Gupta A; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Surgery, University of California San Francisco, San Francisco, CA, USA., Kastner P; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France., Chan S; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France., Gardner JM; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Surgery, University of California San Francisco, San Francisco, CA, USA., Ntranos V; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Miller CN; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Anderson MS; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Schjerven H; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Waterfield MR; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	Science immunology [Sci Immunol] 2023 Oct 27; Vol. 8 (88), pp. eabq3109. Date of Electronic Publication: 2023 Oct 27.
DOI:	10.1126/sciimmunol.abq3109
Abstrakt:	Mutations in the gene encoding the zinc-finger transcription factor Ikaros ( IKZF1 ) 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 Ikzf1 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 Ikzf1 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 IKZF1 mutations.
Databáze:	MEDLINE
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