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[This corrects the article DOI: 10.3389/fimmu.2022.906338.].
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Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection.
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Esquistosomiasis mansoni , Esquistosomiasis , Animales , Antígeno CD11c , Inmunidad , Inflamación , Ratones , Schistosoma mansoniRESUMEN
BACKGROUND: Many commodity pulse oximeters are insufficiently calibrated for patients with darker skin. We demonstrate a quantitative measurement of this disparity in peripheral blood oxygen saturation (SpO2) with a controlled experiment. To mitigate this, we present OptoBeat, an ultra-low-cost smartphone-based optical sensing system that captures SpO2 and heart rate while calibrating for differences in skin tone. Our sensing system can be constructed from commodity components and 3D-printed clips for approximately US $1. In our experiments, we demonstrate the efficacy of the OptoBeat system, which can measure SpO2 within 1% of the ground truth in levels as low as 75%. OBJECTIVE: The objective of this work is to test the following hypotheses and implement an ultra-low-cost smartphone adapter to measure SpO2: skin tone has a significant effect on pulse oximeter measurements (hypothesis 1), images of skin tone can be used to calibrate pulse oximeter error (hypothesis 2), and SpO2 can be measured with a smartphone camera using the screen as a light source (hypothesis 3). METHODS: Synthetic skin with the same optical properties as human skin was used in ex vivo experiments. A skin tone scale was placed in images for calibration and ground truth. To achieve a wide range of SpO2 for measurement, we reoxygenated sheep blood and pumped it through synthetic arteries. A custom optical system was connected from the smartphone screen (flashing red and blue) to the analyte and into the phone's camera for measurement. RESULTS: The 3 skin tones were accurately classified according to the Fitzpatrick scale as types 2, 3, and 5. Classification was performed using the Euclidean distance between the measured red, green, and blue values. Traditional pulse oximeter measurements (n=2000) showed significant differences between skin tones in both alternating current and direct current measurements using ANOVA (direct current: F2,5997=3.1170 × 105, P<.01; alternating current: F2,5997=8.07 × 106, P<.01). Continuous SpO2 measurements (n=400; 10-second samples, 67 minutes total) from 95% to 75% were captured using OptoBeat in an ex vivo experiment. The accuracy was measured to be within 1% of the ground truth via quadratic support vector machine regression and 10-fold cross-validation (R2=0.97, root mean square error=0.7, mean square error=0.49, and mean absolute error=0.5). In the human-participant proof-of-concept experiment (N=3; samples=3 × N, duration=20-30 seconds per sample), SpO2 measurements were accurate to within 0.5% of the ground truth, and pulse rate measurements were accurate to within 1.7% of the ground truth. CONCLUSIONS: In this work, we demonstrate that skin tone has a significant effect on SpO2 measurements and the design and evaluation of OptoBeat. The ultra-low-cost OptoBeat system enables smartphones to classify skin tone for calibration, reliably measure SpO2 as low as 75%, and normalize to avoid skin tone-based bias.
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Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-γ at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs supported Th2 cell responses from infection-experienced CD4+ T cells, a process dependent on pDC IFN-I responsiveness, yet independent of Ag. Together, these data highlight a previously unappreciated role for pDCs and IFN-I in maintaining and reinforcing type 2 immunity in the lymph nodes and inflamed tissue during helminth infection.
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Citocinas/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/parasitología , Citocinas/metabolismo , Células Dendríticas/parasitología , Femenino , Citometría de Flujo/métodos , Interacciones Huésped-Parásitos/inmunología , Recuento de Linfocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/metabolismo , Esquistosomiasis mansoni/parasitología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/parasitología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/parasitologíaRESUMEN
Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.
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Cresta Neural , Síndrome de Pierre Robin , Diferenciación Celular , Humanos , Mutación/genética , Secuencias Reguladoras de Ácidos Nucleicos , Factor de Transcripción SOX9/genéticaRESUMEN
Methyl-CpG-binding domain-2 (Mbd2) acts as an epigenetic regulator of gene expression, by linking DNA methylation to repressive chromatin structure. Although Mbd2 is widely expressed in gastrointestinal immune cells and is implicated in regulating intestinal cancer, anti-helminth responses and colonic inflammation, the Mbd2-expressing cell types that control these responses are incompletely defined. Indeed, epigenetic control of gene expression in cells that regulate intestinal immunity is generally poorly understood, even though such mechanisms may explain the inability of standard genetic approaches to pinpoint the causes of conditions like inflammatory bowel disease. In this study we demonstrate a vital role for Mbd2 in regulating murine colonic inflammation. Mbd2-/- mice displayed dramatically worse pathology than wild type controls during dextran sulfate sodium (DSS) induced colitis, with increased inflammatory (IL-1ß+) monocytes. Profiling of mRNA from innate immune and epithelial cell (EC) populations suggested that Mbd2 suppresses inflammation and pathology via control of innate-epithelial cell crosstalk and T cell recruitment. Consequently, restriction of Mbd2 deficiency to CD11c+ dendritic cells and macrophages, or to ECs, resulted in increased DSS colitis severity. Our identification of this dual role for Mbd2 in regulating the inflammatory capacity of both CD11c+ cells and ECs highlights how epigenetic control mechanisms may limit intestinal inflammatory responses.
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Colitis/etiología , Colon/inmunología , Proteínas de Unión al ADN/fisiología , Células Dendríticas/inmunología , Mucosa Intestinal/inmunología , Animales , Antígenos CD11/análisis , Colitis/inmunología , Susceptibilidad a Enfermedades , Femenino , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , TranscriptomaRESUMEN
Spt6 is a histone chaperone that associates with RNA polymerase II and deposits nucleosomes in the wake of transcription. Although Spt6 has an essential function in nucleosome deposition, it is not known whether this function is influenced by post-translational modification. Here, we report that casein kinase II (CKII) phosphorylation of Spt6 is required for nucleosome occupancy at the 5' ends of genes to prevent aberrant antisense transcription and enforce transcriptional directionality. Mechanistically, we show that CKII phosphorylation of Spt6 promotes the interaction of Spt6 with Spn1, a binding partner required for chromatin reassembly and full recruitment of Spt6 to genes. Our study defines a function for CKII phosphorylation in transcription and highlights the importance of post-translational modification in histone chaperone function.
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Quinasa de la Caseína II/metabolismo , Chaperonas de Histonas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Transcripción Genética , Factores de Elongación Transcripcional/metabolismo , Cromatina/metabolismo , Genoma Fúngico , Chaperonas de Histonas/química , Modelos Biológicos , Nucleosomas/metabolismo , Fosforilación , Unión Proteica , Proteínas de Saccharomyces cerevisiae/química , Factores de Elongación Transcripcional/químicaRESUMEN
Motivated by the need to support those self-managing chronic pain, we report on the development and evaluation of a novel pressure-based tangible user interface (TUI) for the self-report of scalar values representing pain intensity. Our TUI consists of a conductive foam-based, force-sensitive resistor (FSR) covered in a soft rubber with embedded signal conditioning, an ARM Cortex-M0 microprocessor, and Bluetooth Low Energy (BLE). In-lab usability and feasibility studies with 28 participants found that individuals were able to use the device to make reliable reports with four degrees of freedom as well map squeeze pressure to pain level and visual feedback. Building on insights from these studies, we further redesigned the FSR into a wearable device with multiple form factors, including a necklace, bracelet, and keychain. A usability study with an additional 7 participants from our target population, elderly individuals with chronic pain, found high receptivity to the wearable design, which offered a number of participant-valued characteristics (e.g., discreetness) along with other design implications that serve to inform the continued refinement of tangible devices that support pain self-assessment.
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Spt6 is an essential histone chaperone that mediates nucleosome reassembly during gene transcription. Spt6 also associates with RNA polymerase II (RNAPII) via a tandem Src2 homology domain. However, the significance of Spt6-RNAPII interaction is not well understood. Here, we show that Spt6 recruitment to genes and the nucleosome reassembly functions of Spt6 can still occur in the absence of its association with RNAPII. Surprisingly, we found that Spt6-RNAPII association is required for efficient recruitment of the Ccr4-Not de-adenylation complex to transcribed genes for essential degradation of a range of mRNAs, including mRNAs required for cell-cycle progression. These findings reveal an unexpected control mechanism for mRNA turnover during transcription facilitated by a histone chaperone.
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Chaperonas de Histonas/metabolismo , ARN Polimerasa II/metabolismo , ARN Mensajero/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Factores de Elongación Transcripcional/metabolismo , Chaperonas de Histonas/genética , Histonas/genética , Histonas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleosomas/genética , Nucleosomas/metabolismo , ARN Polimerasa II/genética , Estabilidad del ARN , ARN Mensajero/genética , Elementos Reguladores de la Transcripción , Saccharomyces cerevisiae/enzimología , Proteínas de Saccharomyces cerevisiae/genética , Transcripción Genética , Factores de Elongación Transcripcional/genéticaRESUMEN
Multivalent binding is an efficient means to enhance the affinity and specificity of chemical probes targeting multidomain proteins in order to study their function and role in disease. While the theory of multivalent binding is straightforward, physical and structural characterization of bivalent binding encounters multiple technical difficulties. We present a case study where a combination of experimental techniques and computational simulations was used to comprehensively characterize the binding and structure-affinity relationships for a series of Bromosporine-based bivalent bromodomain ligands with a bivalent protein, Transcription Initiation Factor TFIID subunit 1 (TAF1). Experimental techniques-Isothermal Titration Calorimetry, X-ray Crystallography, Circular Dichroism, Size Exclusion Chromatography-Multi-Angle Light Scattering, and Surface Plasmon Resonance-were used to determine structures, binding affinities, and kinetics of monovalent ligands and bivalent ligands with varying linker lengths. The experimental data for monomeric ligands were fed into explicit computational simulations, in which both ligand and protein species were present in a broad range of concentrations, and in up to a 100 s time regime, to match experimental conditions. These simulations provided accurate estimates for apparent affinities (in good agreement with experimental data), individual dissociation microconstants and other microscopic details for each type of protein-ligand complex. We conclude that the expected efficiency of bivalent ligands in a cellular context is difficult to estimate by a single technique in vitro, due to higher order associations favored at the concentrations used, and other complicating processes. Rather, a combination of structural, biophysical, and computational approaches should be utilized to estimate and characterize multivalent interactions.
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Histona Acetiltransferasas/química , Factores Asociados con la Proteína de Unión a TATA/química , Factor de Transcripción TFIID/química , Calorimetría , Cristalografía por Rayos X , Dispersión Dinámica de Luz , Histona Acetiltransferasas/metabolismo , Humanos , Sondas Moleculares/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Factor de Transcripción TFIID/metabolismoRESUMEN
Methylation of histone H3 lysine 36 (H3K36me) by yeast Set2 is critical for the maintenance of chromatin structure and transcriptional fidelity. However, we do not know the full range of Set2/H3K36me functions or the scope of mechanisms that regulate Set2-dependent H3K36 methylation. Here, we show that the APC/CCDC20 complex regulates Set2 protein abundance during the cell cycle. Significantly, absence of Set2-mediated H3K36me causes a loss of cell cycle control and pronounced defects in the transcriptional fidelity of cell cycle regulatory genes, a class of genes that are generally long, hence highly dependent on Set2/H3K36me for their transcriptional fidelity. Because APC/C also controls human SETD2, and SETD2 likewise regulates cell cycle progression, our data imply an evolutionarily conserved cell cycle function for Set2/SETD2 that may explain why recurrent mutations of SETD2 contribute to human disease.
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Ciclosoma-Complejo Promotor de la Anafase/genética , Ciclo Celular/genética , Regulación Fúngica de la Expresión Génica , Metiltransferasas/genética , Procesamiento Proteico-Postraduccional , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Transcripción Genética , Evolución Biológica , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Ciclo Celular/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Metiltransferasas/metabolismo , Nocodazol/farmacología , Proteolisis , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Moduladores de Tubulina/farmacologíaRESUMEN
X-ray micro-computed tomography (µCT) is a technique which can obtain three-dimensional images of a sample, including its internal structure, without the need for destructive sectioning. Here, we review the capability of the technique and examine its potential to provide novel insights into the lifestyles of parasites embedded within host tissue. The current capabilities and limitations of the technology in producing contrast in soft tissues are discussed, as well as the potential solutions for parasitologists looking to apply this technique. We present example images of the mouse whipworm Trichuris muris and discuss the application of µCT to provide unique insights into parasite behaviour and pathology, which are inaccessible to other imaging modalities.
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Imagenología Tridimensional , Parásitos/anatomía & histología , Microtomografía por Rayos X , Animales , Ratones , Tricuriasis/diagnóstico por imagen , Trichuris/anatomía & histologíaRESUMEN
H2A.Z is a histone H2A variant that contributes to transcriptional regulation, DNA damage response and limits heterochromatin spreading. In Saccharomyces cerevisiae, H2A.Z is deposited by the SWR-C complex, which relies on several histone chaperones including Nap1 and Chz1 to deliver H2A.Z-H2B dimers to SWR-C. However, the mechanisms by which Nap1 and Chz1 cooperate to bind H2A.Z and their contribution to H2A.Z deposition in chromatin is not well understood. Using structural modeling and molecular dynamics simulations, we identify a series of H2A.Z residues that form a chaperone-specific binding surface. Mutation of these residues revealed different surface requirements for Nap1 and Chz1 interaction with H2A.Z. Consistent with this result, we found that loss of Nap1 or Chz1 individually resulted in mild defects in H2A.Z deposition, but that deletion of both Nap1 and Chz1 resulted in a significant reduction of H2A.Z deposition at promoters and led to heterochromatin spreading. Together, our findings reveal unique H2A.Z surface dependences for Nap1 and Chz1 and a redundant role for these chaperones in H2A.Z deposition.
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Chaperonas de Histonas/metabolismo , Proteína 1 de Ensamblaje de Nucleosomas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Chaperonas de Histonas/química , Chaperonas de Histonas/genética , Modelos Moleculares , Proteína 1 de Ensamblaje de Nucleosomas/química , Proteína 1 de Ensamblaje de Nucleosomas/genética , Unión Proteica , Conformación Proteica , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Relación Estructura-ActividadRESUMEN
Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice were incapable of initiating Th2 responses in vivo These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.
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Células Dendríticas/inmunología , Interferón Tipo I/metabolismo , Células Th2/inmunología , Alérgenos/inmunología , Animales , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Receptor de Interferón alfa y beta/deficiencia , Schistosoma mansoni/inmunologíaRESUMEN
Set2-mediated histone methylation at H3K36 regulates diverse activities, including DNA repair, mRNA splicing, and suppression of inappropriate (cryptic) transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased lifespan, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found that the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ) cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.
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Procesamiento Proteico-Postraduccional/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transcripción Genética/genética , MetilaciónRESUMEN
Previous studies indicate that the way we perceive our bodily signals, such as our heart rate, can influence how we feel. Inspired by these studies, we built EmotionCheck, which is a wearable device that can change users' perception of their heart rate through subtle vibrations on the wrist. The results of an experiment with 67 participants show that the EmotionCheck device can help users regulate their anxiety through false feedback of a slow heart rate.
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Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4(+) T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4(+) T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure.
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Células Dendríticas/inmunología , Hígado/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Animales , Antígenos Helmínticos/inmunología , Diferenciación Celular , Células Cultivadas , Células Dendríticas/parasitología , Hígado/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BLRESUMEN
Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.
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Proteínas de Unión al ADN/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/genética , ARN Mensajero/metabolismo , Células Th2/inmunología , Alérgenos , Animales , Linfocitos T CD4-Positivos/inmunología , Polaridad Celular , Inmunoprecipitación de Cromatina , Metilación de ADN , Proteínas de Unión al ADN/genética , Ensayo de Inmunoadsorción Enzimática , Epigénesis Genética , Citometría de Flujo , Hipersensibilidad/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunologíaRESUMEN
The archetypal Th2 cytokine IL-4 has previously been shown to alternatively activate murine macrophages and, more recently, dendritic cells (DCs) both in vitro and in vivo. IL-4 has also been shown to induce Aldh1a2 (aldehyde dehydrogenase 1a2) expression in murine macrophages recruited to the peritoneal cavity. However, the influence of IL-4 on DC Aldh1a2 induction in vivo has not yet been addressed. In this work, we found that DCs show enhanced aldehyde dehydrogenase enzyme activity in vivo, which led us to investigate the impact of the vitamin A metabolite all-trans retinoic acid (RA) on DC alternative activation and function. Antagonism of RA receptors reduced production of resistin-like molecule alpha by DCs responding to IL-4, while addition of exogenous RA enhanced production of this marker of alternative activation. Functionally, RA increased DC induction of CD4(+) T-cell IL-10, while reducing CD4(+) T-cell IL-4 and IL-13, revealing a previously unidentified role for RA in regulating the ability of alternatively activated DCs to influence Th2 polarization.