Erythropoietin receptor on cDC1s dictates immune tolerance
Article Date: 10 December 2025
Article URL: https://www.nature.com/articles/s41586-025-09824-z
Article Image: (not provided)
Summary
This Nature paper reports that erythropoietin (EPO) signalling through the erythropoietin receptor (EPOR) on conventional type 1 dendritic cells (cDC1s) enforces a tolerogenic programme. Using genetic mouse models (Epor flox/flox and Epor ΔXcr1), single-cell and bulk RNA-seq, in vivo transplantation and tumour models, the authors show EPOR+ cDC1s favour regulatory T cell (FOXP3+) induction and blunt cross-priming; loss of EPOR on cDC1s converts them to immunogenic antigen-presenting cells and enhances anti-tumour immunity and graft rejection outcomes.
Key Points
- EPO rises after widespread apoptosis (TLI/ATS) and drives EPOR signalling specifically in a subset of cDC1s, identified as CCR7+ migratory cDC1s.
- EPOR activation in cDC1s promotes a tolerogenic transcriptional programme and supports induction/maintenance of FOXP3+ regulatory T cells via TGFβ and other mediators.
- Epor ΔXcr1 mice show reduced tumour growth (MC38-OVA, B16F10-OVA) and increased effector CD8+ T cell function in tumours, linking cDC1 EPOR signalling to tumour tolerance mechanisms.
- The work uses scRNA-seq, CODEX imaging, genetic loss-of-function models and functional T cell assays to connect EPOR signalling in cDC1s to systemic tolerance, transplantation chimerism and tumour immunity.
Content summary
The authors observed a surge in serum EPO after treatments that cause widespread apoptosis (total lymphoid irradiation + anti-thymocyte serum). A subset of migratory CCR7+ cDC1s expresses EPOR and, when signalled by EPO, adopts molecular signatures associated with tolerogenic antigen presentation and FOXP3+ regulatory T cell induction.
Genetic deletion of Epor specifically in cDC1s (Epor ΔXcr1) prevented activation of EPO downstream signalling in these cells. Epor-deficient cDC1s upregulated costimulatory molecules and antigen-presentation programmes, increasing both CD8+ cross-priming and CD4+ priming to cell-associated antigen. Functionally, loss of EPOR on cDC1s reduced transplant tolerance in the TLI/ATS model and limited growth of implanted tumours, while enhancing cytotoxic T cell responses in tumour-draining lymph nodes and tumours.
Mechanistically, tolerogenic activity by EPOR+ cDC1s depended on TGFβ-driven FOXP3 induction and metabolic/ signalling changes captured by bulk and single-cell transcriptomics. The paper provides processed scRNA-seq and bulk RNA-seq datasets (GEO GSE284080 and GSE253056) and analysis code on GitHub and Synapse for reproducibility.
Context and relevance
This study connects a classic haematopoietic hormone (EPO) to adaptive immune tolerance via dendritic cells. It expands prior work showing EPO effects on macrophages to a key antigen-presenting dendritic cell subset (cDC1), which is central to cross-presentation and anti-tumour immunity. The findings are relevant to multiple fields:
- Transplantation: explains a pathway that may be harnessed or blocked to tune graft tolerance.
- Cancer immunology: identifies EPOR on cDC1s as a mechanism that can suppress anti-tumour T cell responses — a potential target to boost immunotherapy.
- Autoimmunity and tolerance biology: highlights how tissue damage and consequent EPO release can program dendritic cells to promote peripheral tolerance.
Why should I read this?
Short and blunt: if you care about how dendritic cells decide between tolerance and immunity — and who doesn’t these days? — this paper gives you a neat, actionable mechanism. It links a familiar systemic signal (EPO) to cDC1 behaviour with solid in vivo genetics and single-cell charts, plus practical implications for transplantation and cancer. We’ve saved you the slog of wading through the methods: the headline is that blocking EPOR on cDC1s can flip the immune switch from tolerant to immunogenic.