Homeostatic maturation programs drive human cDC2s into a tolerogenic state

  • Immunity. 2026 May 12;59(5):1201-1220.e13. doi: 10.1016/j.immuni.2026.01.028.
Mengmeng Lu  1 ,  Runpeng Han  1 ,  Hao Yang  1 ,  Lin Yang  2 ,  Qiuchen Zhao  3 ,  Jun Wang  3 ,  Zhenyang Yu  3 ,  Na Liu  3 ,  Yangyang Xu  3 ,  Fei Luo  3 ,  Yitong Mu  3 ,  Hao Wang  4 ,  Fang Luo  3 ,  Zhenyu Wang  5 ,  Minjie Zhou  5 ,  Kuozeng Lin  5 ,  Hang Chen  6 ,  Honglei Chen  6 ,  Wei Zhou  7 ,  Xiong Chen  3 ,  Hanjie Li  8 ,  Renjin Chen  9 ,  Qing Zhang  10 ,  Li Wang  11 ,  Liang Cheng  12
Affiliations
  • 1. Department of Otolaryngology, Head and Neck Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan 430071, China; Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 2. Department of General Surgery, Xuzhou Mine Hospital, Xuzhou 221000, China.
  • 3. Department of Otolaryngology, Head and Neck Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan 430071, China.
  • 4. Maternal Fetal Medicine Institute, Department of Obstetrics and Gynaecology, Shenzhen Baoan District Women's and Children's Hospital, Jinan University, Shenzhen 518101, China.
  • 5. Cancer Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 6. Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 7. Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430071, China.
  • 8. Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 9. School of Life Science, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 10. Cancer Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: [email protected].
  • 11. Department of Otolaryngology, Head and Neck Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan 430071, China; Department of Cardiology, Institute of Myocardial Injury and Repair, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 12. Department of Otolaryngology, Head and Neck Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan 430071, China; Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
PMID: 41713421 DOI: 10.1016/j.immuni.2026.01.028
Abstract

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.

Keywords
dendritic cells; homeostatic maturation; immune tolerance; regulatory T cells; thymic stromal lymphopoietin; tissue- restricted self-antigens.
Products