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.
Sci Immunol. 2023 Oct 27;8(88):eabq3109. doi: 10.1126/sciimmunol.abq3109.
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.
锌指转录因子 Ikaros（）基因的突变可在免疫缺陷、白血病和自身免疫患者中发现。尽管 Ikaros 在调节造血发育相关基因表达程序方面具有明确的功能，但它在其他细胞类型中的作用尚未得到充分定义。在这里，我们揭示了 Ikaros 在小鼠胸腺上皮谱系发育中的功能，并表明髓质胸腺上皮细胞（mTEC）中的 表达对于自身免疫调节因子阳性（Aire）mTEC 的发育和组织特异性抗原（TSA）基因表达都是必需的。因此，在小鼠中特异性地删除 会导致 Aire mTEC 大量减少、TSA 基因表达的全面丧失以及自身免疫的发展。此外，Ikaros 塑造了胸腺拟态细胞的多样性，其缺失导致胸腺簇细胞和肌样 mTEC 的显著扩张，以及其他依赖 Aire 的拟态群体的丧失。单细胞分析表明，Ikaros 调节了 TEC 中的核心转录程序，这些程序与观察到的细胞变化相关。我们的研究结果强调了 Ikaros 在调节上皮谱系发育和功能中的先前未描述的作用，并表明胸腺中枢耐受的失败可能导致携带 突变的人类出现自身免疫。
