Erythropoietin receptor on cDC1s dictates immune tolerance

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.