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

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. Editor's summary: Within the thymus, a heterogeneous population of epithelial cells make proteins normally restricted to cell types found in other organs. By presenting antigens derived from these proteins, the epithelial cells contribute to the process of deleting T cells within the thymus, avoiding the release of autoreactive immune cells into the rest of the body. Sin et al. investigated what transcription factors, beyond those currently known, may control the development and function of thymic epithelial cells. Deletion of Ikaros in mice changed the development of specific subsets of thymic epithelial cells and decreased expression of tissue-specific antigens, resulting in the presence of autoreactive T cells within tissues. This function in central tolerance might, therefore, contribute to mutations in Ikaros in humans being associated with autoimmunity. —Sarah H. Ross [ABSTRACT FROM AUTHOR]