Immunity · 2026
Homeostatic maturation programs drive human cDC2s into a tolerogenic state.
СтатьяНазвание и аннотация: Перевод в очереди
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Lu Mengmeng, Han Runpeng, Yang Hao, Yang Lin, Zhao Qiuchen, Wang Jun, Yu Zhenyang, Liu Na, Xu Yangyang, Luo Fei, Mu Yitong, Wang Hao, Luo Fang, Wang Zhenyu, Zhou Minjie, Lin Kuozeng, Chen Hang, Chen Honglei, Zhou Wei, Chen Xiong, Li Hanjie, Chen Renjin, Zhang Qing, Wang Li, Cheng Liang
Аннотация
Dendritic cells (DCs) serve as central regulators of immune activation and tolerance. While DC-mediated protective immunity is well established, the mechanisms underlying human peripheral tolerance remain unclear. Through the multi-omics analysis of human splenic DC maturation trajectories, we identified a homeostatic maturation program in type 2 conventional DCs (cDC2s). These homeostatically matured cDC2s (DC2hm) demonstrated the coordinated upregulation of (1) tolerance-associated transcripts (including tissue-restricted self-antigens), (2) regulatory T cell (Treg cell)-polarization machinery, and (3) the thymic stromal lymphopoietin (TSLP) receptor complex (interleukin [IL]-7Rα and TSLP receptor [TSLPR]). Functionally, IL-7Rα+CCR7+ DC2hm exhibited potent capacity to convert naive CD4+ T cells into FOXP3+ Treg cells. TSLP stimulation recapitulated the DC2hm phenotype in human ex vivo models and humanized mice, establishing this cytokine as a critical regulator of DC-mediated tolerance. Our findings delineate a human cDC2 homeostatic maturation program and identify DC2hm as potential mediators of human peripheral tolerance, providing insights into autoimmune disease mechanisms and tolerance-inducing therapeutic strategies.