COUP-TFII-mediated reprogramming of the vascular endothelium counteracts tumor immune evasion.

T cell scarcity in tumor tissues poses a critical challenge to cancer immunotherapy. Here we manipulate the tumor vasculature, an essential regulator of immune cell trafficking, to reinvigorate anti-tumor T cell responses in "cold" tumors. We show that ectopic pan-endothelial expression of COUP-TFII, a master transcription factor for venous development, induces molecular programs of post-capillary venules in tumor endothelium.

Common Gene Networks Orchestrate Organelle Architecture and Inter-Organelle Metabolic Flows for Mucin Production in High Endothelial and Goblet Cells.

High endothelial cells (HECs) and intestinal goblet cells (GCs) are highly specialized through organelle expansion and metabolism for production of sulfated mucins essential for lymphocyte homing and mucosal defense, respectively. How these cells coordinate organelle architecture and biosynthetic pathways to support such demands remains poorly understood. Here, we show at single-cell resolution that HECs rely on gene regulatory networks driven by IRE1α-XBP1 and CREB3L1/2 transcription factors.

Plasmon-activated water enhances gut-barrier function and alleviates inflammation in a mouse model of ulcerative colitis.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by disruption of the intestinal epithelial barrier and alterations in mucosal gene expression associated with intestinal integrity. Given the risks associated with UC, novel therapies capable of restoring intestinal barrier function and inhibiting inflammation are needed. Plasmon-activated water (PAW) is a nontoxic form of water with potential in the treatment of inflammatory diseases.

An SSTR2-somatostatin chemotactic axis drives T cell progenitor homing to the intestines.

Progenitors of intraepithelial T cells (IELps) migrate from the thymus to the intestines after birth where they develop into unconventional TCRγδ and TCRαβ lymphocytes in a process of extrathymic lymphopoiesis within cryptopatches. Mechanisms of IELp migration have remained unclear. Here we show that thymic IELps express the somatostatin receptor SSTR2, which contributes to their homing to the gut.

Navigating SARS-CoV-2-related immunopathology in Crohn's disease: from molecular mechanisms to therapeutic challenges.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not only posed major health and economic burdens to international societies but also threatens patients with comorbidities and underlying autoimmune disorders, including Crohn's disease (CD) patients. As the vaccinated population is gradually relieved from the stress of the latest omicron variant of SARS-CoV-2 due to competent immune responses, the anxiety of CD patients, especially those on immunosuppressive treatment, has not subsided. Whether the use of immunosuppressants for remission of CD outweighs the potential risk of severe coronavirus disease 2019 (COVID-19) has long been discussed.

A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.

Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon and skin are known, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the non-intestinal mucosal tissues and distinguishes them from intestinal mucosae.

Nitrifying niche in estuaries is expanded by the plastisphere.

The estuarine plastisphere, a novel ecological habitat in the Anthropocene, has garnered global concerns. Recent geochemical evidence has pointed out its potential role in influencing nitrogen biogeochemistry. However, the biogeochemical significance of the plastisphere and its mechanisms regulating nitrogen cycling remain elusive.

Endothelial cell Notch signaling programs cancer-associated fibroblasts to promote tumor immune evasion.

Stromal cells within the tumor tissue promote immune evasion as a critical strategy for cancer development and progression, but the underlying mechanisms remain poorly understood. In this study, we explore the role of endothelial cells (ECs) in the regulation of the immunosuppressive tumor microenvironment. Using mouse pancreatic ductal adenocarcinoma (PDAC) models, we found that canonical Notch signaling in endothelial cells suppresses the recruitment of antitumor T cells and promotes tumor progression by inhibiting the pro-inflammatory functions of cancer-associated fibroblasts (CAFs).

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation.

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation.

Transcription factor induction of vascular blood stem cell niches in vivo.

The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche.

An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression.

Immunoglobulin family and carbohydrate vascular addressins encoded by Madcam1 and St6gal1 control lymphocyte homing into intestinal tissues, regulating immunity and inflammation. The addressins are developmentally programmed to decorate endothelial cells lining gut post-capillary and high endothelial venules (HEV), providing a prototypical example of organ- and segment-specific endothelial specialization. We identify conserved NKX-COUP-TFII composite elements (NCCE) in regulatory regions of Madcam1 and St6gal1 that bind intestinal homeodomain protein NKX2-3 cooperatively with venous nuclear receptor COUP-TFII to activate transcription.

Estuarine plastisphere as an overlooked source of NO production.

"Plastisphere", microbial communities colonizing plastic debris, has sparked global concern for marine ecosystems. Microbiome inhabiting this novel human-made niche has been increasingly characterized; however, whether the plastisphere holds crucial roles in biogeochemical cycling remains largely unknown. Here we evaluate the potential of plastisphere in biotic and abiotic denitrification and nitrous oxide (NO) production in estuaries.

Development of follicular dendritic cells in lymph nodes depends on retinoic acid-mediated signaling.

Specialized stromal cells occupy and help define B- and T-cell domains, which are crucial for proper functioning of our immune system. Signaling through lymphotoxin and TNF receptors is crucial for the development of different stromal subsets, which are thought to arise from a common precursor. However, mechanisms that control the selective generation of the different stromal phenotypes are not known.

The aryl hydrocarbon receptor regulates expression of mucosal trafficking receptor GPR15.

GPR15 is a chemoattractant receptor that facilitates colon homing of regulatory and effector CD4 T cells in health and colitis. The molecular mechanisms that control GPR15 expression are not fully known. Here we report the presence of two highly conserved aryl hydrocarbon receptor (AHR) binding sequences in a 3' enhancer of GPR15, leading us to investigate AHR function in regulating GPR15 expression.

A molecular map of murine lymph node blood vascular endothelium at single cell resolution.

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature.

A Single-Cell Transcriptional Roadmap of the Mouse and Human Lymph Node Lymphatic Vasculature.

Single-cell transcriptomics promise to revolutionize our understanding of the vasculature. Emerging computational methods applied to high-dimensional single-cell data allow integration of results between samples and species and illuminate the diversity and underlying developmental and architectural organization of cell populations. Here, we illustrate these methods in the analysis of mouse lymph node (LN) lymphatic endothelial cells (LEC) at single-cell resolution.

Retinoic Acid and Lymphotoxin Signaling Promote Differentiation of Human Intestinal M Cells.

Background & Aims: Intestinal microfold (M) cells are a unique subset of intestinal epithelial cells in the Peyer's patches that regulate mucosal immunity, serving as portals for sampling and uptake of luminal antigens. The inability to efficiently develop human M cells in cell culture has impeded studies of the intestinal immune system. We aimed to identify signaling pathways required for differentiation of human M cells and establish a robust culture system using human ileum enteroids.

Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils.

Lymphatic vessels form a critical component in the regulation of human health and disease. While their functional significance is increasingly being recognized, the comprehensive heterogeneity of lymphatics remains uncharacterized. Here, we report the profiling of 33,000 lymphatic endothelial cells (LECs) in human lymph nodes (LNs) by single-cell RNA sequencing.

A dipeptidyl peptidase-4 inhibitor promotes wound healing in normoglycemic mice by modulating keratinocyte activity.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a well-known and novel class of oral antihyperglycaemic drugs. DPP-4 inhibition facilitates ulcer healing in patients with diabetes. However, the actual mechanisms, which are independent of lower blood glucose levels, are still unknown.

A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15.

Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived sushi containing domain-2 binding factor (CSBF), encoded by in the human and in the mouse, functions as a chemokine ligand for GPR15 (GPR15L).

Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo.

Unlabelled: Circulating factor VIII (FVIII) is derived from liver and from extrahepatic sources probably of endothelial origin, but the vascular sites of FVIII production remain unclear. Among organs profiled, only liver and lymph nodes (LNs) show abundant expression of F8 messenger RNA (mRNA). Transcriptomic profiling of subsets of stromal cells, including endothelial cells (ECs) from mouse LNs and other tissues, showed that F8 mRNA is expressed by lymphatic ECs (LECs) but not by capillary ECs (capECs), fibroblastic reticular cells, or hematopoietic cells.

Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.

Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon.

Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing.

Lymphocytes are recruited from blood by high-endothelial venules (HEVs). We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization. Capillaries expressed gene programs for vascular development.

Orphan chemoattractant receptor GPR15 mediates dendritic epidermal T-cell recruitment to the skin.

Homing of murine dendritic epidermal T cells (DETCs) from the thymus to the skin is regulated by specific trafficking receptors during late embryogenesis. Once in the epidermis, Vγ3δ1 TCR DETCs are maintained through self-renewal and participate in wound healing. GPR15 is an orphan G protein-linked chemoattractant receptor involved in the recruitment of regulatory T cells to the colon.