Center for Immunology, Department of Lab Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Research Informatics Solutions, Laboratory Medicine and Pathology Group, Minnesota Supercomputing Institute, Minneapolis, MN 55455, USA.
Sci Immunol. 2024 Jul 26;9(97):eadp1139. doi: 10.1126/sciimmunol.adp1139.
Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE murine thymic epithelial cells, independent of microbial stimulation. Antigen-presenting cells were highly responsive to thymic IFNs, and IFNs were required for the activation and maturation of thymic type 1 conventional dendritic cells, macrophages, and B cells. Loss of IFN sensing led to reduced regulatory T cell selection, reduced T cell receptor (TCR) repertoire diversity, and enhanced autoreactive T cell responses to self-antigens expressed during peripheral IFN signaling. Thus, constitutive exposure to IFNs in the thymus is required for generating a tolerant and diverse TCR repertoire.
I 型和 III 型干扰素 (IFNs) 在感染期间被强烈诱导，可保护细胞免受病毒感染。I 型和 III 型 IFN 在静息状态下也在胸腺中以低水平持续产生；然而，它们在 T 细胞发育和免疫耐受中的作用尚不清楚。在这里，我们发现 I 型和 III 型 IFN 均由一小部分 AIRE 小鼠胸腺上皮细胞组成，独立于微生物刺激而持续产生。抗原呈递细胞对胸腺 IFN 高度敏感，IFN 对于胸腺 1 型传统树突状细胞、巨噬细胞和 B 细胞的激活和成熟是必需的。IFN 感应缺失导致调节性 T 细胞选择减少，T 细胞受体 (TCR) 库多样性减少，以及外周 IFN 信号传导过程中表达的自身抗原的自身反应性 T 细胞反应增强。因此，胸腺中持续暴露于 IFN 是产生耐受和多样化 TCR 库所必需的。
