In a groundbreaking study published in Nature in 2025, researchers have unveiled a pivotal mechanism by which type 1 conventional dendritic cells (cDC1s) regulate immune tolerance, mediated by the erythropoietin receptor (EPOR). This discovery sheds new light on the sophisticated ways the immune system balances defenses against pathogens and tumors with the prevention of autoimmune reactions.
cDC1s, a distinct subset of dendritic cells, possess unique capabilities critical for immune regulation. Notably, they excel in efferocytosis—the clearance of apoptotic cells—and in cross-presentation, a process essential for activating antigen-specific T cells. These functions enable cDC1s to promote either immunity or tolerance, a dual role that has puzzled immunologists for years. The current study decisively positions EPOR as a molecular switch modulating these divergent outcomes.
The research team employed a comprehensive approach involving total lymphoid irradiation, a method known to induce allograft tolerance, to observe EPOR dynamics in cDC1 populations. They found that EPOR expression is markedly upregulated in splenic cDC1s under these conditions. Strikingly, when EPOR was genetically ablated specifically in cDC1s, mice failed to induce and expand FOXP3-positive regulatory T (T_reg) cells, key players in maintaining immune self-tolerance. Consequently, these mice experienced allograft rejection, underscoring EPOR’s indispensable role in promoting tolerance.
Further mechanistic insights revealed that EPOR drives a tolerogenic maturation program in cDC1s following efferocytosis. This transition leads to the emergence of late-stage CCR7-positive cDC1s characterized by elevated expression of the integrin β8 gene (Itgb8), crucial for functional maturation. Ablation of Itgb8 in cDC1s similarly impaired tolerance induction, confirming its role downstream of EPOR signaling.
Peripheral lymph nodes were also scrutinized in the study, where migratory cDC1s showed preferential EPOR expression. Supplementation with erythropoietin enhanced these migratory cells’ capacity to induce FOXP3-positive T_reg cells ex vivo, reinforcing the concept that EPOR signaling potentiates immune tolerance not only in the spleen but also in peripheral lymphoid tissues.
Conversely, the loss of EPOR in cDC1s shifts their phenotype towards immunogenic maturation. This switch is marked by enhanced expression of genes involved in both MHC class I and class II antigen presentation, cross-presentation, and co-stimulatory pathways. Such changes amplify antigen-specific effector T cell responses, providing a mechanistic basis for EPOR’s role as a gatekeeper of immune balance.
One of the most compelling implications of this work lies in cancer immunology. EPOR deficiency in cDC1s led to reduced tumor growth, attributed to augmented antitumor T cell responses. Notably, there was an increase in precursor exhausted tumor antigen-specific CD8-positive T cells within tumor-draining lymph nodes, suggesting improved priming and maintenance of these critical immune effectors. Simultaneously, intratumoral T_reg cells were diminished, further tipping the balance toward tumor eradication.
The dualistic nature of EPOR signaling in cDC1s presents exciting therapeutic possibilities. In autoimmune diseases and transplantation, promoting EPOR activity could foster tolerance, preventing detrimental immune attacks. Conversely, inhibiting EPOR in cDC1s might enhance anti-tumor immunity by preventing tolerogenic maturation and fueling effector T cell responses, paving a new avenue in cancer immunotherapy.
This research also places cDC1s at the forefront of immune modulation strategies. Their unique ability to fine-tune immune outcomes through EPOR-dependent pathways invites a reevaluation of dendritic cell-targeted therapies. Modulating EPOR expression or signaling could become a precision tool to either amplify immune tolerance or invigorate immune activation depending on clinical needs.
At the molecular level, the interaction between EPOR and integrin β8 highlights a previously unappreciated axis in dendritic cell biology. Integrin β8’s involvement in TGF-β activation, a key cytokine in immunoregulation, provides a mechanistic link to how EPOR facilitates a tolerogenic microenvironment conducive to T_reg cell expansion and function.
Future studies will likely explore how erythropoietin administration or EPOR modulation affects human immune diseases. Given the conserved roles of EPOR across species and the clinical availability of erythropoietin analogs, translating these findings into therapeutic interventions may be accelerated, offering hope for patients suffering from transplantation rejection, autoimmune disorders, or cancer.
Moreover, the discovery that EPOR expression delineates distinct maturational states of cDC1s adds a vital layer to our understanding of dendritic cell heterogeneity. It suggests that microenvironmental cues, such as signals from apoptotic cells and inflammatory mediators, converge on EPOR pathways to dictate dendritic cell fate decisions, with far-reaching consequences for immune tolerance and activation.
In summary, the identification of EPOR as a critical determinant of cDC1 function integrates immunological, cellular, and molecular insights into a coherent framework explaining how immune tolerance is orchestrated. This work not only deepens our grasp of immune homeostasis but also unveils a promising target for manipulating immune responses in diverse clinical contexts.
As research progresses, harnessing the immunomodulatory potential of the erythropoietin-EPOR axis in cDC1s promises transformative advances in immunotherapy, heralding a new era where precise control of dendritic cell function can dictate therapeutic success across multiple diseases.
Subject of Research: Regulation of immune tolerance by erythropoietin receptor signaling on type 1 conventional dendritic cells (cDC1s).
Article Title: Erythropoietin receptor on cDC1s dictates immune tolerance.
Article References:
Zhang, X., McGinnis, C.S., Yu, G. et al. Erythropoietin receptor on cDC1s dictates immune tolerance. Nature (2025). https://doi.org/10.1038/s41586-025-09824-z
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