Erythropoietin receptor on cDC1s dictates immune tolerance.

Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis(1) and cross-presenting abilities(2), resulting in antigen-specific T cell immunity(3) 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. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation(7,11) of splenic cDC1s towards late-stage CCR7(+) cDC1s characterized by increased expression of the integrin β8 gene(12) (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3(+) T(reg) cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7(+) cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8(+) T cells(13) in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural T(reg) cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.