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Erythropoietin receptor on cDC1s dictates immune tolerance

ABSTRACT: Immune tolerance is an active state of unresponsiveness of the immune system to antigens (Ags) that have the potential to induce an immune response1. Such tolerance is beneficial in avoiding autoimmunity and rejection of organ transplants, 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 state of cDC1s and the threshold of Ag-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance11,12, EpoR+ cDC1s induce donor-specific CD4+FoxP3+ regulatory T cells (Tregs), and conditional knockout of EpoR in cDC1s abrogates Ag-specific Treg induction, resulting in allograft rejection. In the steady state, EpoR+ migratory cDC1s control Ag-specific Treg induction in peripheral lymph nodes (LNs). In cancer, EpoR is expressed on both tumor Ag-carrying, tumor-infiltrating cDC1s, as well as migratory cDC1s in tumor-draining LNs (tdLNs). Loss of EpoR from cDC1s leads to tumor reduction by enhancing tumor Ag-specific CD8+ T cell priming and generating more precursor exhausted T cells13 in tdLNs, preserving CD8+ T cell precursor-like features and effector function, and reducing Tregs in the tumor. Thus, targeting EpoR on cDC1s to induce or inhibit immune tolerance should enable new ways to treat a variety of diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE253056 | GEO | 2024/03/01

REPOSITORIES: GEO

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Project description:Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing T-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of co-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, B-cells) and T-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which co-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and co-stimulation blockade (CTLA-4 Ig, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (Balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received co-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (cDC1s and cDC2s). Compared to the cyclosporine treated group, these cells expressed negative regulators of T-cell stimulation including PDL1. Using recipient mice that lack either cDC1s or cDC2s, we found that cDC1s are absolutely required for co-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart.

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Erythropoietin receptor on cDC1s dictates immune tolerance

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