Poster Presentation 18th International Symposium on Dendritic Cells 2026

Erythropoietin receptor on cDC1s dictates immune tolerance (#225)

Xiangyue Zhang 1 , Christopher S McGinnis 1 2 , Guotao Yu 1 , Sijie Chen 1 , Pingping Zheng 1 , Christian M Schürch 3 4 , Kamir J Hiam-Galvez 1 , Nathan E Reticker-Flynn 1 , Wenhui Guo 1 , Winnie Yao 1 , Jingtao Qiu 1 , Alexander Muselman 1 , Ian L Linde 1 , John W Hickey 5 , Hao Yan 1 , Victoria M Tran 6 , Wenli Qiu 7 , Delphine Brichart-Vernos 8 , Toshihito Hirai 1 , Bo Yu 9 , Xiuli An 10 , Yanling Xiao 11 , Helena Paidassi 8 , Tiffany C Scharschmidt 7 , Michael Angelo 1 , Dean Sheppard 7 , Hongbo Chi 12 , Ansuman T Satpathy 1 2 , Sing Sing Way 13 , Bernard Malissen 14 , Samuel Strober 1 , Edgar G Engleman 1
  1. Stanford University, Palo Alto, CALIFORNIA, United States
  2. Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
  3. Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
  4. Cluster of Excellence iFIT (EXC 2180), Image-Guided and Functionally Instructed Tumor Therapies, Tübingen, Germany
  5. Biomedical Engineering, Duke University, Durham, North Carolina, USA
  6. Dermatology, University of California, San Francisco, San Francisco, California, USA
  7. Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep, University of California, San Francisco, San Francisco, California, USA
  8. Centre International de Recherche en Infectiologie, Université de Lyon, Lyon, France
  9. ImmunEdge Inc, Redwood City, California, USA
  10. Laboratory of Membrane Biology, New York Blood Center, New York, USA
  11. Immunology, Leiden University Medical Center, Leiden, The Netherlands
  12. Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, USA
  13. Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  14. Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université, INSERM, CNRS, , Marseille, France

Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis1 and cross-presenting abilities2, resulting in antigen (Ag)-specific T cell immunity3 or tolerance4-8. However, the mechanisms underlying cDC1 tolerogenic function remain largely unknown. Here, we show that the erythropoietin receptor (EpoR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of Ag-specific T cell responses. In total lymphoid (TLI)-induced allograft tolerance9,10, cDC1s upregulate EpoR expression, and conditional knockout of EpoR in cDC1s diminishes Ag-specific FOXP3+ Treg induction and expansion, resulting in allograft rejection. Mechanistically, EpoR promotes efferocytosis-induced tolerogenic maturation7,11 of splenic cDC1s towards late-stage CCR7⁺ cDC1s characterized by elevated integrin β8 gene12 (Itgb8) expression, and conditional knockout of Itgb8 in cDC1s impairs TLI/ATS-induced tolerance. Migratory cDC1s in peripheral lymph nodes (pLNs) preferentially express EpoR and their FOXP3⁺ Treg inducing capacity is enhanced by EPO. Reciprocally, loss of EpoR enables immunogenic maturation of both pLN migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated Ag presentation, cross-presentation, and costimulation. EpoR deficiency in cDC1s reduces tumor growth by enhancing anti‑tumor T‑cell immunity, particularly increasing the generation of precursor exhausted tumor Ag‑specific CD8⁺ T cells (Tpex)13 in tumor draining LNs and supporting their maintenance within tumors, while concurrently reducing intratumoral Tregs. Targeting EpoR on cDC1s to induce or inhibit T cell immune tolerance could pave the way for treating a variety of diseases. (Nature volume 650, pages 470–480 (2026) https://www.nature.com/articles/s41586-025-09824-z)