biostudies-literatureUnknown650(8101)Zhang XType 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis¹ and cross-presenting abilities², resulting in antigen-specific T cell immunity³ or tolerance^4-8. However, the mechanisms that underlie 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 antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance^9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3⁺ regulatory T (T_reg) cells, resulting in allograft rejection. MechanisticaNature470-480https://www.ebi.ac.uk/biostudies/studies/S-EPMC12929016biostudies-literatureErythropoietin receptor on cDC1s dictates immune tolerance.PMC12929016Qiu JAngelo MEngleman EGGuo WYu GMcGinnis CSChi HHickey JWQiu WWay SSScharschmidt TCAn XChen SPaidassi HHiam-Galvez KJBrichart-Vernos DXiao YZheng PHirai TYao WMalissen BTran VMYu BSchurch CMZhang XStrober SMuselman ASatpathy ATReticker-Flynn NELinde ILYan HSheppard DfalseErythropoietin receptor on cDC1s dictates immune tolerance.Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis¹ and cross-presenting abilities², resulting in antigen-specific T cell immunity³ or tolerance^4-8. However, the mechanisms that underlie 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 antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance^9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3⁺ regulatory T (T_reg) cells, resulting in allograft rejection. Mechanistica2026-01-01T00:00:00Z2026 Feb2026-07-16T18:28:17.49Z2026-07-09T11:14:40.769ZS-EPMC129290164137241510.1038/s41586-025-09824-z