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Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor‐induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen‐specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor‐induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor‐released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential. In this study, we use our recently developed 3D DC‐tumor co‐culture system to investigate how patient‐derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen‐based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor‐corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T‐cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14+ CD1c+ CD163+) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti‐IL‐6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL‐6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor‐induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches. [ABSTRACT FROM AUTHOR]

Anogenital inflammation is a critical risk factor for HIV acquisition. The primary preventative HIV intervention, pre-exposure prophylaxis (PrEP), is ineffective in blocking transmission in anogenital inflammation. Pre-existing sexually transmitted diseases (STIs) and anogenital microbiota dysbiosis are the leading causes of inflammation, where inflammation is extensive and often asymptomatic and undiagnosed. Dendritic cells (DCs), as potent antigen-presenting cells, are among the first to capture HIV upon its entry into the mucosa, and they subsequently transport the virus to CD4 T cells, the primary HIV target cells. This increased HIV susceptibility in inflamed tissue likely stems from a disrupted epithelial barrier integrity, phenotypic changes in resident DCs and an influx of inflammatory HIV target cells, including DCs and CD4 T cells. Gaining insight into how HIV interacts with specific inflammatory DC subsets could inform the development of new therapeutic strategies to block HIV transmission. However, little is known about the early stages of HIV capture and transmission in inflammatory environments. Here, we review the currently characterised inflammatory-tissue DCs and their interactions with HIV.

This pioneering agricultural project introduces an intricately integrated system that harnesses IoT technology and automation to transform traditional farming practices. The system relies on a network of sensors to continuously gather real-time data on temperature and humidity, as well as rain conditions within the agricultural environment. A central data hub, equipped with advanced data analysis capabilities, processes this data and historical information to facilitate informed and proactive decision-making. Sophisticated control algorithms govern critical components such as the motorized pulley system and irrigation, ensuring efficient crop protection and resource management. Operating as a highly adaptive and responsive system, it maintains a feedback loop to monitor the effects of its actions and alert farmers to critical conditions. The project provides a user-friendly interface for farmers to customize settings, track system activities, and intervene when necessary.Incorporating machine learning and AI, the system continually enhances control strategies, enhancing efficiency and sustainability. This integrated approach significantly reduces the need for manual intervention, effectively responding to dynamic weather conditions and optimizing crop yields while promoting responsible resource utilization. This innovation represents a significant advancement in modern agriculture, poised to benefit farmers and the environment. [ABSTRACT FROM AUTHOR]

Exploiting inflammasome activation in dendritic cells (DCs) is a promising approach to fight cancer and to augment adjuvant‐induced immune responses. As inflammasome formation is typically accompanied by pyroptosis, hyperactivation—defined as inflammasome activation in the absence of pyroptosis—represents a mechanism of circumventing cell death of DCs while simultaneously benefitting from inflammasome signaling. We previously demonstrated a unique specialization for inflammasome responses and hyperactivation of human cDC2 among all human DC subsets. As recent investigations revealed heterogeneity among the human cDC2 population, we aimed to analyze whether the two recently identified cDC2 subpopulations DC2 and DC3 harbor similar or different inflammasome characteristics. Here, we report that both DC2 and DC3 are inflammasome competent. We show that DC3 generally induce stronger inflammasome responses, which are associated with higher levels of cell death. Although DC2 release lower levels of inflammasome‐dependent IL‐1β, they induce stronger CD4+ T cell responses than DC3, which are predominantly skewed toward a TH1/TH17 phenotype. Thus, mainly DC2 seem to be able to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capacity. [ABSTRACT FROM AUTHOR]

We examine three case studies during the Deep Convective Clouds and Chemistry (DC3) field experiment when storm inflow and outflow air were sampled for aerosol subsaturated hygroscopicity and the real part of refractive index (n) with a Differential Aerosol Sizing and Hygroscopicity Probe (DASH-SP) on the NASA DC-8. Relative to inflow aerosol particles, outflow particles were more hygroscopic (by 0.03 based on the estimated κ parameter) in one of the three storms examined. Two of three “control” flights with no storm convection reveal higher κ values, albeit by only 0.02, at high altitude (> 8 km) versus < 4 km. Entrainment modeling shows that measured κ values in the outflow of the three storm flights are higher than predicted values (by 0.03-0.11) based on knowledge of κ values from the inflow and clear air adjacent to the storms. This suggests that other process(es) contributed to hygroscopicity enhancements such as secondary aerosol formation via aqueous-phase chemistry. Values of n were higher in the outflow of two of the three storm flights, reaching as high as 1.54. More statistically significant differences were observed in control flights (no storms) where n decreased from 1.50-1.52 (< 4 km) to 1.49-1.50 (> 8 km). Chemical data show that enhanced hygroscopicity was coincident with lower organic mass fractions, higher sulfate mass fractions, and higher O: C ratios of organic aerosol. Refractive index did not correlate as well with available chemical data. Deep convection is shown to alter aerosol radiative properties, which has implications for aerosol effects on climate.

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300c iCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c -traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3 CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c -traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses. [Display omitted] • A Cd300c fate mapper mouse traces bone marrow progenitors of pDC and cDC2 • Cd300c expressing bone marrow pro-cDC2 encompass pDC-like and pre-cDC2 • pDC-like have a lymphoid origin, whereas pre-cDC2 derive from myeloid precursors • pDC-like and pre-cDC2 converge into similar cDC2 distinct from pro-DC3-derived DC3 cDC2 and their precursors exhibit heterogeneity, yet the role of ontogeny remains unclear. Rodrigues et al. show that Cd300c labels a bone marrow cDC2 progenitor, which encompasses lymphoid-derived pDC-like and myeloid-derived pre-cDC2. Both progenitors converge into transcriptionally uniform cDC2, distinct from pro-DC3-derived DC3, and are vital for humoral antigen responses. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are professional antigen-presenting cells that develop from hematopoietic stem cells. Different DC subsets exist based on ontogeny, location and function, including the recently identified proinflammatory DC3 subset. DC3 have the prominent activity to polarize CD8+ T cells into CD8+ CD103+ tissue resident T cells. Here we describe human DC3 differentiated from induced pluripotent stem cells (iPS cells). iPS cell-derived DC3 have the gene expression and surface marker make-up of blood DC3 and polarize CD8+ T cells into CD8+ CD103+ tissue-resident memory T cells in vitro. To test the impact of malignant JAK2 V617F mutation on DC3, we differentiated patient-specific iPS cells with JAK2 V617Fhet and JAK2 V617Fhom mutations into JAK2 V617Fhet and JAK2 V617Fhom DC3. The JAK2 V617F mutation enhanced DC3 production and caused a bias toward erythrocytes and megakaryocytes. The patient-specific iPS cell-derived DC3 are expected to allow studying DC3 in human diseases and developing novel therapeutics.

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo. Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14+ myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14+CD1c+ DC-like cells in humanized mouse models. We found that CD14+CD1c+ cells were phenotypically different from cDC2s; CD14+CD1c+ cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14+CD1c+ cells primed and polarized naïve CD4+ T cells toward IFN-γ+ Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14+CD1c+ cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14+CD1c+ cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14+CD1c+ DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo.

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo. Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14+ myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14+CD1c+ DC-like cells in humanized mouse models. We found that CD14+CD1c+ cells were phenotypically different from cDC2s; CD14+CD1c+ cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14+CD1c+ cells primed and polarized naïve CD4+ T cells toward IFN-γ+ Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14+CD1c+ cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14+CD1c+ cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14+CD1c+ DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo. [ABSTRACT FROM AUTHOR]

Over the last decade, multiple studies have investigated the heterogeneity of murine conventional dendritic cells type 2 (cDC2s). However, their phenotypic similarity with monocytes and macrophages renders their clear identification challenging. By creating a protein atlas utilizing multiparameter flow cytometry, we show that ESAM+ cDC2s are a specialized feature of the spleen strongly differing in their proteome from other cDC2s. In contrast, all other tissues are populated by Clec12A+ cDC2s or Clec12A− cDC2s (high or low for Fcγ receptors, C-type lectin receptors, and CD11b, respectively), rendering Clec12A+ cDC2s classical sentinels. Further, expression analysis of CD301b, Clec12A, and FcγRIIB/III provides a conserved definition of cDC2 heterogeneity, including the discovery of putative FcγRIIB/III+ DC3s across tissues. Finally, our data reveal that cell identity (ontogeny) dictates the proteome that is further fine-tuned by the tissue environment on macrophages and dendritic cells (DCs), while monocytes and plasmacytoid DCs (pDCs) display subset intrinsic default settings. [Display omitted] • A surface protein library delineates cDC2 heterogeneity across tissues • ESAM+ cDC2s are a specialized feature of the spleen • The splenic cDC2 compartment is unrepresentative for the cross-tissue cDC2 network • Tissue cDC2 repertoires are subcategorized by Clec12A, CD301b, and FcγRIIB/III Dendritic cells are central regulators of the immune system. Amon et al. analyzed the cDC compartment across multiple murine tissues, focusing on cDC2 heterogeneity. They delineated ESAM+ cDC2s as a specialized feature of the spleen, while cDC2 heterogeneity in all tissues was multilayered and defined by Clec12A, CD301b, and FcγRIIB/III. [ABSTRACT FROM AUTHOR]

Di Pilato et al. demonstrate that CXCR6 positions TCF-1− transitory CD8+ cytotoxic lymphocytes (CTLs) with perivascular CCR7+ dendritic cells (DCs) within the tumor stroma to receive IL-15 survival signals. The requirement for CXCR6 and its strong prediction of overall patient survival highlight the importance of continued CTL–DC interactions in sustaining tumor immunity. [ABSTRACT FROM AUTHOR]

Abstract: This study reports a characterization of the real part of dry particle refractive index (n) at 532 nm based on airborne measurements over the United States, Canada, the Pacific Ocean, and the Gulf of Mexico from the 2012 Deep Convective Clouds and Chemistry (DC3) and 2013 Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) campaigns. Effective n values are reported, with the limitations and uncertainties discussed. Eight air mass types were identified based on criteria related to gas‐phase tracer concentrations, location, and altitude. Average values of n for these air types ranged from 1.50 to 1.53. Values of n for the organic aerosol (OA) fraction (nOA) were calculated using a linear mixing rule for each air mass type, with 1.52 shown to be a good approximation for all OA. Case studies detailing vertical structure revealed that n and nOA increased with altitude, simultaneous with enhancements in the mass fraction of OA. Values of nOA were positively (negatively) correlated with the O:C (H:C) ratio in the absence of biomass burning influence; in contrast, the cumulative data set revealed a slight decrease in nOA as a function of the O:C ratio. The performance of parametric (multiple linear regression) and nonparametric (Gaussian process regression) methods in predicting n based on aerosol composition data is discussed. It is shown that even small perturbations in n values significantly impact aerosol optical depth retrievals, radiative forcing, and optical sizing instruments, emphasizing the importance of further improving the understanding of this important aerosol property. [ABSTRACT FROM AUTHOR]

Abstract: The microphysical characteristics of deep convective storms are a critically important, yet difficult aspect of storm morphology to observe in situ. These observations play a large role in several areas of ongoing research, but detailed observations in key portions of clouds do not exist with the currently available measurement platforms. To facilitate these observations, a balloon‐borne particle imaging device known as the PArticle Size, Image, and Velocity (PASIV) probe was developed at the National Severe Storms Laboratory, which is capable of measuring particle counts on scales as small as 50 m. The videosonde observations from the PASIV showed that precipitation particle counts change rapidly between analysis layers, sometimes by as much as a few orders of magnitude (102–104 in adjacent layers), and radar reflectivities calculated directly from observed particle size distributions agree with mobile radar measurements. Furthermore, the observations allow the distributions to be partitioned into various particle types, which sheds light on which particles are dominating the radar signal at various times. These distributions per particle type, and their associated mixing ratios, agree with independent model analysis. Additionally, single‐, double‐, and triple‐moment parameterized particle size distribution functions are fit to various layers, with the general result that ice particles are easily represented by exponential distributions while rain is better fit with a gamma distribution. The parametric fits for ice and rain distributions found here support previous work and some portions of modeled microphysics, but also suggest room for improvement when deciding which schemes to use with cloud modeling. [ABSTRACT FROM AUTHOR]

Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32+CD172a+ DC3, distinct from DC2, arising from Ly6C+ monocyte-DC progenitors (MDPs) through Lyz2+Ly6C+CD11c− pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7+Ly6C+CD11c+ pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s. [Display omitted] • CSF1R+Ly6C+FLT3+CD11c− "R2" cells are DC progenitors, not monocytes • Expressions of CD45RB and FLT3 distinguish DCs from monocytes • Lyz2+ DC progenitors (pro-DC3s) give rise to DC3s • DC3 is an independent lineage of DCs arising from Ly6C+ monocyte-DC progenitors Delineating the lineage development of dendritic cells (DCs) is challenging as these cells show overlapping phenotypes with monocytes and other cells. Using single-cell sequencing and fate mapping approaches, Liu et al. demonstrate that murine DCs develop through three lineages, with DC3s developing from Ly6C+ monocyte-dendritic cell progenitors (MDPs) through pro-DC3s. [ABSTRACT FROM AUTHOR]

Lightning is one of the most important sources of upper tropospheric NO x; however, there is a large spread in estimates of the global emission rates (2-8 Tg N yr−1). We combine upper tropospheric in situ observations from the Deep Convective Clouds and Chemistry (DC3) experiment and global satellite-retrieved NO2 tropospheric column densities to constrain mean lightning NO x (LNO x) emissions per flash. Insights from DC3 indicate that the NO x lifetime is ~3 h in the region of outflow of thunderstorms, mainly due to production of methyl peroxy nitrate and alkyl and multifunctional nitrates. The lifetime then increases farther downwind from the region of outflow. Reinterpreting previous analyses using the 3 h lifetime reduces the spread among various methods that have been used to calculate mean LNO x emissions per flash and indicates a global LNO x emission rate of ~9 Tg N yr−1, a flux larger than the high end of recent estimates. [ABSTRACT FROM AUTHOR]

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5−CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies. • InfinityFlow protein expression analysis reveals DC- and monocyte-specific markers • Monocytes are CD88+CD89+, while cDC2s are HLA-DQ+FcεRIα+ • cDC2s comprise CD5+ DC2s and CD5−CD163+/−CD14+/− DC3s • Pro-inflammatory CD14+ DC3 expansion correlates with disease activity in SLE patients Using high-dimensional protein and RNA single-cell analyses, Dutertre et al. analyze human dendritic cell and monocyte subsets and identify markers that delineate them and unravel their heterogeneity. They also reveal the presence of inflammatory CD14+ DC3s, a subset of cDC2s, that correlate with disease progression and may be functionally involved in systemic lupus erythematosus immunopathology. [ABSTRACT FROM AUTHOR]