Erythropoietin receptor on cDC1s dictates immune tolerance

ABSTRACT: Immune tolerance1 is beneficial in transplantation and autoimmunity but detrimental in cancer2. Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis3 and cross-presenting abilities4, resulting in T cell-mediated immunity5 or tolerance6-10. 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 antigen (Ag)-specific T cell responses. In total lymphoid irradiation and anti-thymocyte serum (TLI/ATS)-induced allograft tolerance11,12, 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 integrin β8 gene (Itgb8) expression, and conditional knockout of Itgb8 in cDC1s impairs TLI/ATS-induced tolerance. Migratory cDC1s in peripheral lymph nodes preferentially express EpoR, and their capacity to induce FOXP3⁺ Tregs is enhanced by EPO stimulation. Reciprocally, EpoR deficiency enables immunogenic maturation of both pLN migratory and splenic CCR7⁺ cDC1s by upregulating genes essential for MHC class II-mediated Ag presentation, 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 cells13 in tumor draining lymph nodes 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: GSE253056 | GEO | 2024/03/01

REPOSITORIES: GEO