TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells

Nature Immunology · 2025-08-12 · 11 citations

Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.

Thymic myeloid cells are heterogenous and include a novel population of transitional dendritic cells

The Journal of Experimental Medicine · 2025-08-27 · 5 citations

Myeloid cells, including dendritic cells (DCs) and macrophages, are essential for establishing central tolerance in the thymus by promoting T cell clonal deletion and regulatory T cell (Treg) generation. Previous studies suggest that the thymic DC pool consists of plasmacytoid DC (pDC), XCR1+ DC1, and SIRPα+ DC2. Yet the precise origin, development, and homeostasis, particularly of DC2, remain unresolved. Using single-cell transcriptomics and lineage-defining mouse models, we identify nine major populations of thymic myeloid cells and describe their lineage identities. What was previously considered to be "DC2" is actually composed of four distinct cell lineages. Among these are monocyte-derived DCs (moDCs) and monocyte-derived macrophages (moMacs), which are dependent on thymic IFN to upregulate MHCII and CD11c. We further demonstrate that conventional DC2 undergo intrathymic maturation through CD40 signaling. Finally, amongst DC2, we identify a novel thymic population of CX3CR1+ transitional DC (tDC), which represents transendothelial DCs positioned near thymic microvessels. Together, these findings reveal the thymus as a niche for diverse, developmentally distinct myeloid cells and elucidate their specific requirements for development and maturation.

Thymic DC2 are heterogenous and include a novel population of transitional dendritic cells

bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-18 · 1 citations

Abstract Myeloid cells, including dendritic cells (DCs) and macrophages, are essential for establishing central tolerance in the thymus by promoting T cell clonal deletion and regulatory T cell (Treg) generation. Previous studies suggest that the thymic DC pool consists of plasmacytoid DC (pDC), XCR1 + DC1 and SIRPα + DC2. Yet the precise origin, development, and homeostasis, particularly of DC2, remain unresolved. Using single-cell transcriptomics and lineage-defining mouse models we identify nine major populations of thymic myeloid cells and describe their lineage identities. What was previously considered to be “DC2” is actually composed of 4 distinct cell lineages. Amongst these are monocyte-derived DCs (moDC) and monocyte derived macrophages (moMac), which are dependent on thymic interferon to upregulate MHCII and CD11c. We further demonstrate that conventional DC2 undergo intrathymic maturation through CD40 signaling. Finally, amongst “DC2” we identify a novel thymic population of CX3CR1 + transitional DC (tDC), which represent transendothelial DCs positioned near thymic microvessels. Together, these finding reveal the thymus as a niche for diverse, developmentally distinct myeloid cells and elucidate their specific requirements for development and maturation.

Chemokine-chemokine receptor networks in conventional type I dendritic cells: an opportunity to prime and boost anticancer immunity

Journal of Pharmacology and Experimental Therapeutics · 2025-09-25 · 1 citations

Bridging <scp>pDCs</scp> and <scp>cDCs</scp> : The Identity of Transitional Dendritic Cells

Immunological Reviews · 2025-11-01 · 2 citations

ABSTRACT Transitional dendritic cells (tDCs) have emerged as a compelling addition to the dendritic cell (DC) network—a hybrid subset that bridges plasmacytoid (pDC) and conventional (cDC) lineages, particularly conventional type 2 DCs (cDC2s). First identified through high‐dimensional single‐cell profiling, tDCs combine features of both pDCs and cDC2s yet follow a distinct developmental trajectory with unique effector functions. Although ontogenetically related to pDCs, tDCs do not produce type I interferon but instead mount a robust IL‐1β response upon pathogen sensing, positioning them as rapid initiators of innate inflammation. tDCs also mirror cDC2s in their ability to capture antigen and prime naïve CD4 + T cells. Importantly, tDCs exist in progressive states—tDC lo , tDC hi , CD11b − tDC2s and tDC‐derived DC2s (tDC2s)—reflecting a unidirectional differentiation continuum. Recognizing this dynamic spectrum is essential for properly interpreting tDC function and avoiding fragmented nomenclature. In this review, we synthesize current insights into tDC biology across species—tracing their origin, phenotypic and transcriptional trajectory, tissue localization, and immune function. Although tDCs challenge the rigid pDC/cDC dichotomy, they exemplify a broader principle: DC identity is not fixed but temporally programmed, even during homeostasis. Embracing this plasticity may unlock new opportunities for therapeutic intervention in infection, cancer, and autoimmunity.

Publisher Correction: TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells

Nature Immunology · 2025-09-05

CD301b+ monocyte-derived dendritic cells mediate resistance to radiotherapy

The Journal of Experimental Medicine · 2025-03-27 · 10 citations

Monocytes infiltrating tumors acquire various states that distinctly impact cancer treatment. Here, we show that resistance of tumors to radiotherapy (RT) is controlled by the accumulation of monocyte-derived dendritic cells (moDCs). These moDCs are characterized by the expression of CD301b and have a superior capacity to generate regulatory T cells (Tregs). Accordingly, moDC depletion limits Treg generation and improves the therapeutic outcome of RT. Mechanistically, we demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from radioresistant tumor cells following RT is necessary for the accumulation of moDCs. Our results unravel the immunosuppressive function of moDCs and identify GM-CSF as an immunotherapeutic target during RT.

Antibody-Based Antigen Delivery to Dendritic Cells as a Vaccination Strategy Against Ebola Virus Disease

The Journal of Infectious Diseases · 2025-01-14 · 2 citations

Dendritic cells connect innate and adaptive immune responses. This is a particularly important immune checkpoint in the case of emerging infections against which most of the population does not have preexisting antibody immunity. In this study, we sought to test whether antibody-based delivery of Ebola virus (EBOV) antigens to dendritic cells could be used as a vaccination strategy against Ebola virus disease. Our approach was to use antibodies targeting the endocytic receptor DEC-205 present in murine and human dendritic cells, to deliver the EBOV nucleoprotein or the model antigen ovalbumin (OVA). Our findings indicate that DEC-205 targeting stimulated antigen-specific T-cell responses in mice, which resulted in protection from EBOV or recombinant EBOV-OVA challenge. An added value of this strategy was the generation of resident memory T cells. We propose that dendritic cell targeting could be used to improve T-cell responses against filoviruses, a strategy that may complement current vaccination strategies.

Tonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells

Nature Immunology · 2025-10-14 · 3 citations

Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small 'IFN-I-naive' subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the 'IFN-I-primed' subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses.

Thymic DC2 are heterogenous and include a novel population of transitional dendritic cells 3216

The Journal of Immunology · 2025-11-01

Abstract Description Myeloid cells, including dendritic cells (DCs) and macrophages, are essential for establishing central tolerance in the thymus by promoting T cell clonal deletion and regulatory T cell (Treg) generation. Previous studies suggest that the thymic DC pool consists of plasmacytoid DC (pDC), XCR1+ DC1 and SIRPa+ DC2. Yet the precise origin, development, and homeostasis, particularly of DC2, remain unresolved. Using single-cell transcriptomics and lineage-defining mouse models we identify nine major populations of thymic myeloid cells and describe their lineage identities. We show that thymus SIRPa+ DC population contain subsets of monocyte-derived cells–DCs (moDC), and monocyte derived macrophages (moMac), that are dependent on thymic interferons (IFNs). We further demonstrate that conventional DC2 undergo intrathymic maturation regulated by CD40 signaling. Finally, we identify a novel thymic population of CX3CR1+ transitional DC (tDC) amongst SIRPa+ DC that represent transedothelial DCs positioned near thymic microvessels enabling presentation of blood-born antigens in the thymus. Together, these finding reveal the thymus as a niche for diverse, developmentally distinct myeloid cells and elucidate their specific requirements for development and maturation. Funding Sources Cancer Research Institute Irvington Postdoctoral Fellowship (CRI4536) Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)