-
Science (New York, N.Y.) Apr 2024Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity...
Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
Topics: Female; Male; Androgens; Dendritic Cells; Gonadal Steroid Hormones; Immunity, Innate; Lymphocytes; Sex Characteristics; Skin; Animals; Mice; Mice, Inbred C57BL; Microbiota
PubMed: 38574174
DOI: 10.1126/science.adk6200 -
Nature Dec 2023People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown....
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Chromatin; Dendritic Cells; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Glucose; Histones; Hyperglycemia; Lung; T-Lymphocytes; Virus Diseases; Viruses; Disease Models, Animal; Humans
PubMed: 38093014
DOI: 10.1038/s41586-023-06803-0 -
Science Immunology Jul 2023T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs,...
T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs, which travel from the tissue to the lymph node, not only drive initial T cell activation but also transfer antigen to lymph node-resident cDCs. These resident cells have essential roles defining the character of the resulting T cell response; however, it is unknown how they can appropriately process and present antigens to suitably direct responses given their spatial separation. Here, using a novel strain of influenza A and a modified melanoma model, we show that tissue and lymph node cDC activation is harmonized and that this is driven by cotransfer of contextual cues. In the tumor, incomplete cDC activation in the tumor microenvironment is mirrored by lymph node-resident cDCs, whereas during influenza infection, pathogen-associated molecular patterns cotransferred with antigen drive TLR signaling in resident cDCs and their subsequent robust activation. This cotransfer mechanism explains how individual antigens can be handled distinctly by resident cDCs and how signals driving poor tumoral cDC activation further impact the lymph node. Our findings clarify how tissue context dictates antigenic and, consequently, T cell fate in the lymph node.
Topics: Humans; Influenza, Human; Dendritic Cells; Antigens; Lymph Nodes; T-Lymphocytes
PubMed: 37478193
DOI: 10.1126/sciimmunol.adg8249 -
Science Translational Medicine Oct 2023Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are...
Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-betEomesCD8 T cells and CD16 natural killer (NK) cells and an increase in putative tolerogenic CD141CD163 DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ (IFN-γ) CD4 and CD8 T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8 T cells, as well as attenuation of cytolytic T1 effector genes and pathways among intragraft CD8 T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.
Topics: Humans; CD8-Positive T-Lymphocytes; Liver Transplantation; Dendritic Cells; Living Donors; Killer Cells, Natural; Interferon-gamma; Graft Rejection
PubMed: 37820009
DOI: 10.1126/scitranslmed.adf4287 -
Science Immunology Dec 2023Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling...
Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8 T cell responses. Specifically, CD8 T cell priming capacity was enhanced by MAVS ablation in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8 T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8 T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs.
Topics: Humans; Interleukin-12; CD8-Positive T-Lymphocytes; Signal Transduction; Neoplasms; Dendritic Cells
PubMed: 38039379
DOI: 10.1126/sciimmunol.adf4919 -
Nature Cancer Feb 2024Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens...
Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.
Topics: Humans; Mice; Animals; Cytokines; Immunotherapy; Dendritic Cells; Neoplasms; Interleukin-12
PubMed: 37996514
DOI: 10.1038/s43018-023-00668-y -
Immunity Aug 2023Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph...
Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph nodes (LNs) are short lived and continuously replaced by DC precursors (preDCs) from the bone marrow (BM). Here, we examined whether specific anatomical niches exist within which preDCs differentiate toward immature cDCs. In situ photoconversion and Prtn3-based fate-tracking revealed that the LN medullary cords are preferential entry sites for preDCs, serving as specific differentiation niches. Repopulation and fate-tracking approaches demonstrated that the cDC1 network unfolded from the medulla along the vascular tree toward the paracortex. During inflammation, collective maturation and migration of resident cDC1s to the paracortex created discontinuity in the medullary cDC1 network and temporarily impaired responsiveness. The decrease in local cDC1 density resulted in higher Flt3L availability in the medullary niche, which accelerated cDC1 development to restore the network. Thus, the spatiotemporal development of the cDC1 network is locally regulated in dedicated LN niches via sensing of cDC1 densities.
Topics: Lymph Nodes; Cell Differentiation; Macrophages; Dendritic Cells
PubMed: 37463581
DOI: 10.1016/j.immuni.2023.06.020 -
Nature Reviews. Clinical Oncology Apr 2024Dendritic cells (DCs) are a heterogeneous group of antigen-presenting innate immune cells that regulate adaptive immunity, including against cancer. Therefore,... (Review)
Review
Dendritic cells (DCs) are a heterogeneous group of antigen-presenting innate immune cells that regulate adaptive immunity, including against cancer. Therefore, understanding the precise activities of DCs in tumours and patients with cancer is important. The classification of DC subsets has historically been based on ontogeny; however, single-cell analyses are now additionally revealing a diversity of functional states of DCs in cancer. DCs can promote the activation of potent antitumour T cells and immune responses via numerous mechanisms, although they can also be hijacked by tumour-mediated factors to contribute to immune tolerance and cancer progression. Consequently, DC activities are often key determinants of the efficacy of immunotherapies, including immune-checkpoint inhibitors. Potentiating the antitumour functions of DCs or using them as tools to orchestrate short-term and long-term anticancer immunity has immense but as-yet underexploited therapeutic potential. In this Review, we outline the nature and emerging complexity of DC states as well as their functions in regulating adaptive immunity across different cancer types. We also describe how DCs are required for the success of current immunotherapies and explore the inherent potential of targeting DCs for cancer therapy. We focus on novel insights on DCs derived from patients with different cancers, single-cell studies of DCs and their relevance to therapeutic strategies.
Topics: Humans; Neoplasms; Adaptive Immunity; Immunotherapy; Immune Tolerance; Dendritic Cells
PubMed: 38326563
DOI: 10.1038/s41571-024-00859-1 -
Nature Cancer May 2024Successful immunotherapy relies on triggering complex responses involving T cell dynamics in tumors and the periphery. Characterizing these responses remains challenging...
Successful immunotherapy relies on triggering complex responses involving T cell dynamics in tumors and the periphery. Characterizing these responses remains challenging using static human single-cell atlases or mouse models. To address this, we developed a framework for in vivo tracking of tumor-specific CD8 T cells over time and at single-cell resolution. Our tools facilitate the modeling of gene program dynamics in the tumor microenvironment (TME) and the tumor-draining lymph node (tdLN). Using this approach, we characterize two modes of anti-programmed cell death protein 1 (PD-1) activity, decoupling induced differentiation of tumor-specific activated precursor cells from conventional type 1 dendritic cell (cDC1)-dependent proliferation and recruitment to the TME. We demonstrate that combining anti-PD-1 therapy with anti-4-1BB agonist enhances the recruitment and proliferation of activated precursors, resulting in tumor control. These data suggest that effective response to anti-PD-1 therapy is dependent on sufficient influx of activated precursor CD8 cells to the TME and highlight the importance of understanding system-level dynamics in optimizing immunotherapies.
Topics: Animals; Mice; Immunotherapy; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Humans; Neoplasms; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Dendritic Cells; Cell Line, Tumor
PubMed: 38429414
DOI: 10.1038/s43018-024-00734-z -
Nature Immunology Aug 2023High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the...
High-dimensional approaches have revealed heterogeneity amongst dendritic cells (DCs), including a population of transitional DCs (tDCs) in mice and humans. However, the origin and relationship of tDCs to other DC subsets has been unclear. Here we show that tDCs are distinct from other well-characterized DCs and conventional DC precursors (pre-cDCs). We demonstrate that tDCs originate from bone marrow progenitors shared with plasmacytoid DCs (pDCs). In the periphery, tDCs contribute to the pool of ESAM type 2 DCs (DC2s), and these DC2s have pDC-related developmental features. Different from pre-cDCs, tDCs have less turnover, capture antigen, respond to stimuli and activate antigen-specific naïve T cells, all characteristics of differentiated DCs. Different from pDCs, viral sensing by tDCs results in IL-1β secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDCs are a distinct pDC-related subset with a DC2 differentiation potential and unique proinflammatory function during viral infections.
Topics: Animals; Mice; Antiviral Agents; Bone Marrow; Cell Differentiation; Dendritic Cells
PubMed: 37414907
DOI: 10.1038/s41590-023-01545-7