Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR

Altered compensatory cytokine signaling underlies the discrepancy between Flt3–/– and Flt3l–/– mice

The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe i

NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells

NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+CD43−CD73−DLL4+Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells. These findings demonstrate that NOTCH-mediated arterialization of HE is an essential prerequisite for establishing definitive lympho-myeloid program and suggest that exploring molecular pathways that lead to arterial specification may aid in vitro approaches to enhance definitive hematopoiesis from hPSCs

Analysis of the PHYB Gene Sequence in Arabidopsis Lines Identified in a Red-Light Genetic Suppressor Screen

Color poster with text, images, and graphs.The capability to detect the amount and quality of light is critical for plant growth and development. Red and far-red light are detected by the phytochrome (phy) photoreceptors which mediate plant behavior1. The flowering plant Arabidopsis thaliana contains the genes LRB1 and LRB2 (Light-Response BTB 1 and 2) which encode proteins functioning as target adaptors in BTB/Cullin 3 E3 ubiquitin-ligase complexes. These complexes target phytochromes for ubiquitylation and degradation2. The phytochromes are red/far-red light receptors and plants containing mutations of both LRB1 and 2 genes express hypersensitivity to red light due to increases levels of these photoreceptors. In an attempt to identify additional genes involved in red-light response, the Gingerich lab conducted a genetic screen to identify mutations which suppress the phenotype caused by the lrb1 lrb2 double mutations. All suppressor mutants thus far analyzed have had mutations in the PHYB gene, which encodes a phytochrome that functions as the major red-light receptor in Arabidopsis. Over the past year we have sequenced parts of the PHYB gene in 6 suppressor mutants that had not yet been analyzed. Mutations in PHYB are potentially interesting for researchers who study this important mediator of plant environmental responses. Alternatively, absence of a mutation within the PHYB gene in these lines could indicate a mutation in a separate gene involved in red light response, which could lead to the discovery of new genes involved in the response.National Science Foundation-Research in Undergraduate Institutions (RUI) grants (#0919678 and #1354438); National Science Foundation Arabidopsis 2010 Program Grant (MCB-0115870); National Institutes of Health Ruth L. Kirschstein Postdoctoral Fellowship (F32-GM68361); University of Wisconsin--Eau Claire Office of Research and Sponsored Program

Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity

© 2020 The Author(s) Inflammasome activation in dendritic cells (DCs) leads to pyroptosis or hyperactivation. Zhivaki et al. show that in contrast to pyroptotic DCs, hyperactive DCs stimulate durable anti-tumor immunity that eradicates established tumors. These protective responses are intrinsic to cDC1 cells and depend on DC hypermigration and on the inflammasome-dependent cytokine IL-1β

Inflammasomes within hyperactive murine dendritic cells stimulate long-lived T cell-mediated anti-tumor immunity

Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We show that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1β, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy

Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells

Both classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs) are capable of cross-priming CD8+ T cells in response to cell-associated antigens. We found that Ly-6ChiTREML4− monocytes can differentiate into Zbtb46+ Mo-DCs in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) but that Ly-6ChiTREML4+ monocytes were committed to differentiate into Ly-6CloTREML4+ monocytes. Differentiation of Zbtb46+ Mo-DCs capable of efficient cross-priming required both GM-CSF and IL-4 and was accompanied by the induction of Batf3 and Irf4. However, monocytes require IRF4, but not BATF3, to differentiate into Zbtb46+ Mo-DCs capable of cross-priming CD8+ T cells. Instead, Irf4−/− monocytes differentiate into macrophages in response to GM-CSF and IL-4. Thus, cDCs and Mo-DCs require distinct transcriptional programs of differentiation in acquiring the capacity to prime CD8+ T cells. These differences may be of consideration in the use of therapeutic DC vaccines based on Mo-DCs