Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets ...remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.
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► CCR9 controls pDCs numbers in the thymus ► CCR9 is a marker and thymic homing receptor on immature pDCs ► TLR activation or lack of CCR9 prevents thymic clonal deletion by peripheral pDCs ► Peripheral Ag transport to the thymus by endogenous unactivated pDC is CCR9 dependent
Staphylococcus aureus is a skin- and respiratory tract-colonizing bacterium and is the leading cause of community-acquired skin infections. Dissemination of these bacteria into systemic circulation ...causes bacteremia, which has a high mortality rate. Therefore, understanding the immunologic barriers that prevent dissemination is critical to developing novel treatments. In this study, we demonstrate that an S. aureus breach across skin leads to some migration of the pathogen to the draining lymph node, but no further. While subcapsular sinus (SCS) macrophage in lymph nodes were important in detaining S. aureus, a rapid complement-dependent neutrophil recruitment (independent of the SCS macrophage) via high endothelial venules (HEVs) resulted in high numbers of neutrophils that intercepted the bacteria in the lymph nodes. Peripheral Node Addressin together with its two ligands, L-selectin and platelet P-selectin, are critical for recruiting neutrophils via the HEVs. Almost no neutrophils entered the lymph nodes via lymphatics. Neutrophils actively phagocytosed S. aureus and helped sterilize the lymph nodes and prevent dissemination to blood and other organs.
Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of ...chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein–coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin α4β7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.
Summary
Vitamin D (VD3) has been linked to immunological processes, and its supplementation may have a role in treatment or prevention of diseases with underlying autoimmune or pro‐inflammatory ...states. As initiators of the immune responses, dendritic cells (DC) are a potential target of VD3 to dampen autoimmunity and inflammation, but the role of DC in VD3‐mediated immunomodulation in vivo is not understood. In addition to being targets of VD3, DC can provide a local source of bioactive VD3 for regulation of T‐cell responses. Here we review existing studies that describe the tolerogenic potential of VD3 on DC, and discuss them in the context of current understanding of DC development and function. We speculate on mechanisms that might account for the potent but poorly understood tolerogenic activities of VD3 and the role of DC as both targets and sources of this hormone.
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some ...of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
Ag-presenting dendritic cells (DCs) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial ...surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food Ags. The Wnt family of secreted proteins, which control epithelial and hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. In this study, we show that canonical and noncanonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical β-catenin signaling and preferentially induces DC TGF-β and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns, inhibiting proinflammatory cytokine induction in response to TLR ligands and promoting DC generation of Foxp3(+) regulatory T cells. Moreover, although both Wnts suppress proinflammatory responses to bacterial endotoxin and to TLR1/2, TLR7, and TLR9 ligands, Wnt5A, but not Wnt3A, inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Thus, Wnt family members directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental Ags.
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. Unbiased clustering revealed six major types of human LECs. LECs lining the subcapsular sinus (SCS) of LNs abundantly expressed neutrophil chemoattractants, whereas LECs lining the medullary sinus (MS) expressed a C-type lectin CD209. Binding of a carbohydrate Lewis X (CD15) to CD209 mediated neutrophil binding to the MS. The neutrophil-selective homing by MS LECs may retain neutrophils in the LN medulla and allow lymph-borne pathogens to clear, preventing their spread through LNs in humans. Our study provides a comprehensive characterization of LEC heterogeneity and unveils a previously undefined role for medullary LECs in human immunity.
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•Single-cell RNA sequencing of human lymph nodes unveils six types of LECs•LECs lining the floor and ceiling of the SCS, MS, and valve are the main types•LECs of the SCS floor and MS highly express neutrophil chemoattractants•Human MS LECs support neutrophil adhesion in the LN medulla via CD209
Using single-cell RNA sequencing, Takeda and colleagues identify six types of lymphatic endothelial cells (LECs) in human lymph nodes (LNs) mapped to particular locations, including subcapsular and medullary sinuses (SCSs and MSs). CD209 on MS LECs mediates neutrophil adhesion in the human LN medulla, which may prevent pathogen spread through LNs.
Lymphocytes are imprinted during activation with trafficking programs (combinations of adhesion and chemoattractant receptors) that target their migration to specific tissues and microenvironments. ...Cytokines contribute, but, for gut and skin, evolution has cleverly adapted external cues from food (vitamin A) and sunlight (ultraviolet-induced vitamin D3) to imprint lymphocyte homing to the small intestines and T cell migration into the epidermis. Dendritic cells are essential: they process the vitamins to their active metabolites (retinoic acid and 1,25(OH)(2)D3) for presentation with antigen to lymphocytes, and they help export environmental cues through lymphatics to draining lymph nodes, to program the trafficking and effector functions of naive T and B cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and ...genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.
To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.
We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult
mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult
brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.
By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood ...process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.
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