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Erythropoietin receptor on cDC1s dictates immune tolerance

ABSTRACT: Immune tolerance is an active state of unresponsiveness of the immune system to antigens (Ags) that have the potential to induce an immune response. Such tolerance is beneficial in avoiding autoimmunity but detrimental in cancer. Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis and cross-presenting abilities, resulting in T cell-mediated immunity or tolerance. However, the mechanisms underlying the tolerogenic function of cDC1s 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 irradiation-induced allograft tolerance, 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 maturation of splenic cDC1s towards late-stage CCR7⁺ cDC1s characterized by elevated Itgb8 expression, and conditional knockout of ITGB8 in cDC1s impairs TLI/ATS-induced tolerance. In peripheral lymph nodes (pLNs), migratory cDC1s preferentially express EpoR and exogenous EPO administration enhances their Treg induction capacity. In contrast, EpoR deficiency promotes immunogenic maturation in both pLN migratory and splenic CCR7⁺ cDC1s by upregulating genes essential for MHC class II-associated Ag presentation and cross-presentation and costimulation. In cancer, loss of cDC1 EpoR leads to tumor reduction by enhancing tumor Ag-specific CD8+ T cell priming and generating more precursor exhausted T cells in tdLNs and reducing Tregs in the tumor. Targeting EpoR on cDC1s to either induce or inhibit immune tolerance could pave the way for novel treatments of a variety of diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE284080 | GEO | 2025/09/15

REPOSITORIES: GEO

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Project description:Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing T-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of co-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, B-cells) and T-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which co-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and co-stimulation blockade (CTLA-4 Ig, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (Balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received co-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (cDC1s and cDC2s). Compared to the cyclosporine treated group, these cells expressed negative regulators of T-cell stimulation including PDL1. Using recipient mice that lack either cDC1s or cDC2s, we found that cDC1s are absolutely required for co-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart.

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Erythropoietin receptor on cDC1s dictates immune tolerance

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