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Type 2 cytokines in the thymus activate Sirpα+ dendritic cells to promote clonal deletion
Nature Immunology ( IF 30.5 ) Pub Date : 2022-05-30 , DOI: 10.1038/s41590-022-01218-x
Elise R Breed 1 , Matouš Vobořil 1 , Katherine M Ashby 1 , Ryan J Martinez 1 , Lily Qian 1 , Haiguang Wang 1 , Oscar C Salgado 1 , Christine H O'Connor 2 , Kristin A Hogquist 1
Affiliation  

The thymus contains a diversity of dendritic cells (DCs) that exist in defined locations and have different antigen-processing and -presenting features. This suggests that they play nonredundant roles in mediating thymocyte selection. In an effort to eliminate SIRPα+ classic DC2 subsets, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b+ type 2 immune response promoting DCs that are present in the skin-draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b+ cDCs represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, a CD301b+ cDC2 subset demonstrated a type 2 cytokine signature and required steady-state interleukin-4 receptor signaling. Selective ablation of CD301b+ cDC2 subsets impaired clonal deletion without affecting regulatory T cells (Treg cells). The T cell receptor α repertoire sequencing confirmed that a cDC2 subset promotes deletion of conventional T cells with minimal effect on Treg cell selection. Together, these findings suggest that cytokine-induced activation of DCs in the thymus substantially enforces central tolerance.



中文翻译:

胸腺中的 2 型细胞因子激活 Sirpα+ 树突状细胞以促进克隆缺失

胸腺含有多种树突状细胞 (DC),它们存在于确定的位置并具有不同的抗原加工和呈递特征。这表明它们在介导胸腺细胞选择中发挥非冗余作用。为了消除 SIRPα +经典 DC2 亚群,我们发现很大一部分在胸腺中表达表面凝集素 CD301b。这些细胞类似于促进皮肤引流淋巴结中存在的 DC 的CD301b + 2 型免疫反应。与胸腺中其他 DC 亚群的转录和表型比较表明,胸腺 CD301b + cDC 代表一种激活状态,表现出增强的抗原加工和呈递。此外,CD301b +cDC2 子集表现出 2 型细胞因子特征和需要稳态白细胞介素 4 受体信号传导。CD301b + cDC2 子集的选择性消融会损害克隆删除而不影响调节性 T 细胞(T reg细胞)。T 细胞受体 α 库测序证实,cDC2 子集促进常规 T 细胞的缺失,而对 T reg细胞选择的影响最小。总之,这些发现表明,细胞因子诱导的胸腺 DC 激活显着增强了中枢耐受性。

更新日期:2022-05-31
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