Signaling through erythropoietin receptors on cDC1s promotes immune tolerance (141938)
Peripheral immune tolerance is an active state of unresponsiveness to antigens that should elicit an adaptive immune response but are prevented from doing so mainly by antigen-specific Tregs. Total lymphoid irradiation-induced tolerance to allografts, tumor-associated tolerance and maternal-fetal tolerance are all examples of peripheral immune tolerance. Surprisingly, however, the mechanism responsible for inducing such tolerance has remained elusive. Our findings in mouse models reveal that in each of these settings erythropoietin (EPO) signaling through EPO receptors (EPOR) on conventional Type 1 dendritic cells (cDC1s) promotes cDC1 tolerogenic maturation, activation of antigen-specific Tregs and systemic immune tolerance (Zhang et al Nature 2026 PMCID:PMC12929016). In cancer, EPOR-expressing macrophages as well as EPOR-expressing cDC1s contribute to immune evasion and tolerance, and removal of EPOR from these cells results in the activation of tumor-cytotoxic CD8 T cells and tumor regression (Chiu et al Science 2025 PMCID: PMC12110762). Assuming these findings extend to humans, antagonists and agonists targeting EPOR on cDC1s and macrophages may prove useful in the treatment of disorders ranging from cancer and infection to autoimmune disease and allograft rejection.