Publications by authors named "Ulrich H von Andrian"

166 Publications

Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice.

J Control Release 2021 Feb 17. Epub 2021 Feb 17.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia. Electronic address:

The mesenteric lymph nodes (MLN) are a key site for the generation of adaptive immune responses to gut-derived antigenic material and immune cells within the MLN contribute to the pathophysiology of a range of conditions including inflammatory and autoimmune diseases, viral infections, graft versus host disease and cancer. Targeting immunomodulating drugs to the MLN may thus be beneficial in a range of conditions. This paper investigates the potential benefit of targeting a model immunosuppressant drug, mycophenolic acid (MPA), to T cells in the MLN, using a triglyceride (TG) mimetic prodrug approach. We confirmed that administration of MPA in the TG prodrug form (MPA-TG), increased lymphatic transport of MPA-related species 83-fold and increased MLN concentrations of MPA >20 fold, when compared to MPA alone, for up to 4 h in mice. At the same time, the plasma exposure of MPA and MPA-TG was similar, limiting the opportunity for systemic side effects. Confocal microscopy and flow cytometry studies with a fluorescent model prodrug (Bodipy-TG) revealed that the prodrug accumulated in the MLN cortex and paracortex at 5 and 10 h following administration and was highly associated with B cells and T cells that are found in these regions of the MLN. Finally, we demonstrated that MPA-TG was significantly more effective than MPA at inhibiting CD4 and CD8 T cell proliferation in the MLN of mice in response to an oral ovalbumin antigen challenge. In contrast, MPA-TG was no more effective than MPA at inhibiting T cell proliferation in peripheral LN when mice were challenged via SC administration of ovalbumin. This paper provides the first evidence of an in vivo pharmacodynamic benefit of targeting the MLN using a TG mimetic prodrug approach. The TG mimetic prodrug technology has the potential to benefit the treatment of a range of conditions where aberrant immune responses are initiated in gut-associated lymphoid tissues.
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http://dx.doi.org/10.1016/j.jconrel.2021.02.008DOI Listing
February 2021

Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential.

Cell 2021 Jan 16;184(2):441-459.e25. Epub 2020 Dec 16.

The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.
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http://dx.doi.org/10.1016/j.cell.2020.11.028DOI Listing
January 2021

Role of LFA-1 integrin in the control of a lymphocytic choriomeningitis virus (LCMV) infection.

Virulence 2020 Dec;11(1):1640-1655

Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA.

Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8 T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8 T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8 T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection.
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http://dx.doi.org/10.1080/21505594.2020.1845506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714442PMC
December 2020

Cosmc controls B cell homing.

Nat Commun 2020 08 10;11(1):3990. Epub 2020 Aug 10.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc, and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc-null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc-deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc-null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.
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http://dx.doi.org/10.1038/s41467-020-17765-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417590PMC
August 2020

Gamma Interferon Is Required for Clearance but Is Dispensable for T Cell Homing to the Genital Tract.

mBio 2020 03 17;11(2). Epub 2020 Mar 17.

Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA

While there is no effective vaccine against infection, previous work has demonstrated the importance of -specific CD4 T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host's ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ, and IFN-γR NR1 T cells specifically home to sections in the genital tract that contain We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing infection. is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4 T cells are critical for clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against .
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http://dx.doi.org/10.1128/mBio.00191-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078466PMC
March 2020

Immunology-Guided Biomaterial Design for Mucosal Cancer Vaccines.

Adv Mater 2020 Apr 13;32(13):e1903847. Epub 2019 Dec 13.

Department of Medicine, Engineering in Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02139, USA.

Cancer of mucosal tissues is a major cause of worldwide mortality for which only palliative treatments are available for patients with late-stage disease. Engineered cancer vaccines offer a promising approach for inducing antitumor immunity. The route of vaccination plays a major role in dictating the migratory pattern of lymphocytes, and thus vaccine efficacy in mucosal tissues. Parenteral immunization, specifically subcutaneous and intramuscular, is the most common vaccination route. However, this induces marginal mucosal protection in the absence of tissue-specific imprinting signals. To circumvent this, the mucosal route can be utilized, however degradative mucosal barriers must be overcome. Hence, vaccine administration route and selection of materials able to surmount transport barriers are important considerations in mucosal cancer vaccine design. Here, an overview of mucosal immunity in the context of cancer and mucosal cancer clinical trials is provided. Key considerations are described regarding the design of biomaterial-based vaccines that will afford antitumor immune protection at mucosal surfaces, despite limited knowledge surrounding mucosal vaccination, particularly aided by biomaterials and mechanistic immune-material interactions. Finally, an outlook is given of how future biomaterial-based mucosal cancer vaccines will be shaped by new discoveries in mucosal vaccinology, tumor immunology, immuno-therapeutic screens, and material-immune system interplay.
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http://dx.doi.org/10.1002/adma.201903847DOI Listing
April 2020

CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes.

J Exp Med 2019 05 25;216(5):1170-1181. Epub 2019 Mar 25.

Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity.
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http://dx.doi.org/10.1084/jem.20170277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504218PMC
May 2019

Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis.

Immunity 2018 12 13;49(6):1062-1076.e6. Epub 2018 Nov 13.

Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Inflammation and Therapeutic Innovation, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address:

Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.
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http://dx.doi.org/10.1016/j.immuni.2018.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303217PMC
December 2018

T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation.

Cell 2018 11 1;175(5):1307-1320.e22. Epub 2018 Nov 1.

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Microbiome informatics and Therapeutics, MIT, Cambridge, MA 02139, USA. Electronic address:

In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5 ISCs. We show that MHCII Lgr5 ISCs are non-conventional antigen-presenting cells in co-cultures with CD4 T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5 ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5 ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5 ISCs, thus, orchestrate tissue-wide responses to external signals.
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http://dx.doi.org/10.1016/j.cell.2018.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239889PMC
November 2018

Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival.

J Clin Invest 2018 11 2;128(11):4770-4786. Epub 2018 Oct 2.

Transplantation Research Center and.

The targeted delivery of therapeutic drugs to lymph nodes (LNs) provides an unprecedented opportunity to improve the outcomes of transplantation and immune-mediated diseases. The high endothelial venule is a specialized segment of LN vasculature that uniquely expresses peripheral node addressin (PNAd) molecules. PNAd is recognized by MECA79 mAb. We previously generated a MECA79 mAb-coated microparticle (MP) that carries tacrolimus. Although this MP trafficked to LNs, it demonstrated limited therapeutic efficacy in our transplant model. Here, we have synthesized a nanoparticle (NP) as a carrier of anti-CD3, and optimized the conjugation strategy to coat the NP surface with MECA79 mAb (MECA79-anti-CD3-NP) to enhance LN accumulation. As compared with nonconjugated NPs, a significantly higher quantity of MECA79-NPs accumulated in the draining lymph node (DLN). Many MECA79-NPs underwent internalization by T cells and dendritic cells within the LNs. Short-term treatment of murine cardiac allograft recipients with MECA79-anti-CD3-NP resulted in significantly prolonged allograft survival in comparison with the control groups. Prolonged graft survival following treatment with MECA79-anti-CD3-NP was characterized by a significant increase in intragraft and DLN Treg populations. Treg depletion abrogated the prolongation of heart allograft survival. We believe this targeted approach of drug delivery could redefine the methods of administering immune therapeutics in transplantation.
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http://dx.doi.org/10.1172/JCI120923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205374PMC
November 2018

Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids.

Elife 2018 05 31;7. Epub 2018 May 31.

Division of Gastroenterology, Boston Children's Hospital, Boston, United States.

Transport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absorption of the incretin hormone GLP-1. Peptide cargoes covalently fused to glycosphingolipids with ceramide domains containing C6:0 or smaller fatty acids were transported with 20-100-fold greater efficiency across epithelial barriers in vitro and in vivo. This was explained by structure-function of the ceramide domain in intracellular sorting and by the affinity of the glycosphingolipid species for insertion into and retention in cell membranes. In mice, GLP-1 fused to short-chain glycosphingolipids was rapidly and systemically absorbed after gastric gavage to affect glucose tolerance with serum bioavailability comparable to intraperitoneal injection of GLP-1 alone. This is unprecedented for mucosal absorption of therapeutic peptides, and defines a technology with many other clinical applications.
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http://dx.doi.org/10.7554/eLife.34469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980230PMC
May 2018

RORα-expressing T regulatory cells restrain allergic skin inflammation.

Sci Immunol 2018 03;3(21)

Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (T2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (T) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse T led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and T2 cells. Expression of RORα in skin-resident T suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand-related molecule 1 (TL1A), which promotes T functions. DR3 is expressed on both ILC2s and skin-resident T Upon deletion of RORα in skin-resident T, we found that T were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORα in skin-resident T than in peripheral blood circulating T in humans, suggesting that RORα and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.
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http://dx.doi.org/10.1126/sciimmunol.aao6923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912895PMC
March 2018

Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs.

Cancer Immunol Res 2018 04 19;6(4):389-401. Epub 2018 Feb 19.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8 T cells, whereas IFNγ reduced the number of CD11b cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079513PMC
April 2018

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Natural Killer Cells in Vaccination.

Cold Spring Harb Perspect Biol 2018 10 1;10(10). Epub 2018 Oct 1.

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115.

Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes.
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http://dx.doi.org/10.1101/cshperspect.a029488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169816PMC
October 2018

Organism-Level Analysis of Vaccination Reveals Networks of Protection across Tissues.

Cell 2017 Oct 21;171(2):398-413.e21. Epub 2017 Sep 21.

Faculty of Arts & Sciences Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

A fundamental challenge in immunology is to decipher the principles governing immune responses at the whole-organism scale. Here, using a comparative infection model, we observe immune signal propagation within and between organs to obtain a dynamic map of immune processes at the organism level. We uncover two inter-organ mechanisms of protective immunity mediated by soluble and cellular factors. First, analyzing ligand-receptor connectivity across tissues reveals that type I IFNs trigger a whole-body antiviral state, protecting the host within hours after skin vaccination. Second, combining parabiosis, single-cell analyses, and gene knockouts, we uncover a multi-organ web of tissue-resident memory T cells that functionally adapt to their environment to stop viral spread across the organism. These results have implications for manipulating tissue-resident memory T cells through vaccination and open up new lines of inquiry for the analysis of immune responses at the organism level.
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http://dx.doi.org/10.1016/j.cell.2017.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895295PMC
October 2017

Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.

Nat Neurosci 2017 Nov 18;20(11):1549-1559. Epub 2017 Sep 18.

Department of Neurology and Experimental Neurology, Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.
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http://dx.doi.org/10.1038/nn.4643DOI Listing
November 2017

Illuminating vital surface molecules of symbionts in health and disease.

Nat Microbiol 2017 Jun 26;2:17099. Epub 2017 Jun 26.

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

The immunomodulatory surface molecules of commensal and pathogenic bacteria are critical to microorganisms' survival and the host's response. Recent studies have highlighted the unique and important responses elicited by commensal-derived surface macromolecules. However, the technology available to track these molecules in host cells and tissues remains primitive. We report, here, an interdisciplinary approach that uses metabolic labelling combined with bioorthogonal click chemistry (that is, reactions performed in living organisms) to specifically tag up to three prominent surface immunomodulatory macromolecules-peptidoglycan, lipopolysaccharide and capsular polysaccharide-either simultaneously or individually in live anaerobic commensal bacteria. Importantly, the peptidoglycan labelling enables, for the first time, the specific labelling of live endogenous, anaerobic bacteria within the mammalian host. This approach has allowed us to image and track the path of labelled surface molecules from live, luminal bacteria into specific intestinal immune cells in the living murine host during health and disease. The chemical labelling of three specific macromolecules within a live organism offers the potential for in-depth visualization of host-pathogen interactions.
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http://dx.doi.org/10.1038/nmicrobiol.2017.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546223PMC
June 2017

Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis.

Nat Immunol 2017 Jul 29;18(7):753-761. Epub 2017 May 29.

Institute for Cardiovascular Prevention, Ludwig-Maximilians University (LMU), Munich, Germany.

Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa.
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http://dx.doi.org/10.1038/ni.3763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480598PMC
July 2017

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues.

BMC Biol 2017 05 19;15(1):45. Epub 2017 May 19.

Department of Microbiology and Immunobiology & HMS Center for Immune Imaging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.

Background: Intravascular leukocyte recruitment in most vertebrate tissues is restricted to postcapillary and collecting venules, whereas capillaries and arterioles usually support little or no leukocyte adhesion. This segmental restriction is thought to be mediated by endothelial, rather than hemodynamic, differences. The underlying mechanisms are largely unknown, in part because effective tools to distinguish, isolate, and analyze venular endothelial cells (V-ECs) and non-venular endothelial cells (NV-ECs) have been unavailable. We hypothesized that the atypical chemokine receptor DARC (Duffy Antigen Receptor for Chemokines, a.k.a. ACKR1 or CD234) may distinguish V-ECs versus NV-ECs in mice.

Methods: We generated a rat-anti-mouse monoclonal antibody (MAb) that specifically recognizes the erythroid and endothelial forms of native, surface-expressed DARC. Using this reagent, we characterized DARC expression and distribution in the microvasculature of murine tissues.

Results: DARC was exquisitely restricted to post-capillary and small collecting venules and completely absent from arteries, arterioles, capillaries, veins, and most lymphatics in every tissue analyzed. Accordingly, intravital microscopy showed that adhesive leukocyte-endothelial interactions were restricted to DARC venules. DARC was detectable over the entire circumference of V-ECs, but was more concentrated at cell-cell junctions. Analysis of single-cell suspensions suggested that the frequency of V-ECs among the total microvascular EC pool varies considerably between different tissues.

Conclusions: Immunostaining of endothelial DARC allows the identification and isolation of intact V-ECs from multiple murine tissues. This strategy may be useful to dissect the mechanisms underlying segmental microvascular specialization in healthy and diseased tissues and to characterize the role of EC subsets in tissue-homeostasis, immune surveillance, infection, inflammation, and malignancies.
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http://dx.doi.org/10.1186/s12915-017-0381-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438556PMC
May 2017

Maturation of Platelet Function During Murine Fetal Development In Vivo.

Arterioscler Thromb Vasc Biol 2017 06 20;37(6):1076-1086. Epub 2017 Apr 20.

From the Walter Brendel Centre of Experimental Medicine, Munich, Germany (A.M., C.N., I.R., S.K., A.R.M.K., A.F., J.P., M.P., R.I., S.D., M.S.); Division of Neonatology, Hauner Children's University Hospital and Perinatal Centre, Ludwig Maximilians University, Munich, Germany (C.N., A.F., V.W., A.W.F.); Medizinische Klinik und Poliklinik I, Klinikum der Ludwig Maximilians Universität, Munich, Germany (J.P.); Max Planck Institute for Molecular Biomedicine, Münster, Germany (L.K., F.K.); Max PIanck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany (M.M.); Roche Inc, New York, NY (E.Q.); and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA (U.H.v.A.).

Objective: Platelet function has been intensively studied in the adult organism. However, little is known about the function and hemostatic capacity of platelets in the developing fetus as suitable in vivo models are lacking.

Approach And Results: To examine fetal platelet function in vivo, we generated a fetal thrombosis model and investigated light/dye-induced thrombus formation by intravital microscopy throughout gestation. We observed that significantly less and unstable thrombi were formed at embryonic day (E) 13.5 compared with E17.5. Flow cytometry revealed significantly lower platelet counts in E13.5 versus E17.5 fetuses versus adult controls. In addition, fetal platelets demonstrated changed activation responses of surface adhesion molecules and reduced P-selectin content and mobilization. Interestingly, we also measured reduced levels of the integrin-activating proteins Kindlin-3, Talin-1, and Rap1 during fetal development. Consistently, fetal platelets demonstrated diminished spreading capacity compared with adults. Transfusion of adult platelets into the fetal circulation led to rapid platelet aggregate formation even in young fetuses. Yet, retrospective data analysis of a neonatal cohort demonstrated no correlation of platelet transfusion with closure of a persistent ductus arteriosus, a process reported to be platelet dependent.

Conclusions: Taken together, we demonstrate an ontogenetic regulation of platelet function in vivo with physiologically low platelet numbers and hyporeactivity early during fetal development shedding new light on hemostatic function during fetal life.
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http://dx.doi.org/10.1161/ATVBAHA.116.308464DOI Listing
June 2017

The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis.

Immunity 2016 12 6;45(6):1270-1284. Epub 2016 Dec 6.

Department of Microbiology and Immunobiology and HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA; The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address:

Infections induce pathogen-specific T cell differentiation into diverse effectors (Teff) that give rise to memory (Tmem) subsets. The cell-fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8 Teff and Tmem subsets. Classical central (Tcm) and effector memory (Tem) cells and their corresponding Teff precursors were CX3CR1 and CX3CR1, respectively. Viral infection also induced a numerically stable CX3CR1 subset that represented ∼15% of blood-borne Tmem cells. CX3CR1 Tmem cells underwent more frequent homeostatic divisions than other Tmem subsets and not only self-renewed, but also contributed to the expanding CX3CR1 Tcm pool. Both Tcm and CX3CR1 cells homed to lymph nodes, but CX3CR1 cells, and not Tem cells, predominantly surveyed peripheral tissues. As CX3CR1 Tmem cells present unique phenotypic, homeostatic, and migratory properties, we designate this subset peripheral memory (tpm) cells and propose that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues.
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http://dx.doi.org/10.1016/j.immuni.2016.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177508PMC
December 2016

IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease.

JCI Insight 2016 Aug;1(12)

Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/c mice, models an inflammatory subset of SSc characterized by a prominent IL13-induced gene expression signature in the skin. Host mice deficient in IL4RA, a subunit of the type II IL4/IL13 receptor, are protected from sclGvHD. While IL4RA has a well-established role in Th2 differentiation and alternative macrophage activation, we report here a previously unappreciated function for IL4RA in lymphatic endothelial cells (LECs): regulation of activated T cell egress. Seven days after splenocyte transfer, hosts had increased numbers of activated graft CD4 T cells in skin draining lymph nodes (dLNs) but fewer T cells in efferent lymph, blood, and skin. Sphingosine-1 phosphate (S1P), master regulator of lymphocyte egress from LNs, was lower in dLNs of hosts with a corresponding decrease of S1P kinase 1 () expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4 T cells from dLNs of sclGvHD mice restored clinical GvHD in secondary recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.
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http://dx.doi.org/10.1172/jci.insight.88057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988402PMC
August 2016

Prolonged contact with dendritic cells turns lymph node-resident NK cells into anti-tumor effectors.

EMBO Mol Med 2016 09 1;8(9):1039-51. Epub 2016 Sep 1.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy Humanitas Clinical and Research Center, Rozzano (MI), Italy

Natural killer (NK) cells are critical players against tumors. The outcome of anti-tumor vaccination protocols depends on the efficiency of NK-cell activation, and efforts are constantly made to manipulate them for immunotherapeutic approaches. Thus, a better understanding of NK-cell activation dynamics is needed. NK-cell interactions with accessory cells and trafficking between secondary lymphoid organs and tumoral tissues remain poorly characterized. Here, we show that upon triggering innate immunity with lipopolysaccharide (LPS), NK cells are transiently activated, leave the lymph node, and infiltrate the tumor, delaying its growth. Interestingly, NK cells are not actively recruited at the draining lymph node early after LPS administration, but continue their regular homeostatic turnover. Therefore, NK cells resident in the lymph node at the time of LPS administration become activated and exert anti-tumor functions. NK-cell activation correlates with the establishment of prolonged interactions with dendritic cells (DCs) in lymph nodes, as observed by two-photon microscopy. Close DC and NK-cell contacts are essential for the localized delivery of DC-derived IL-18 to NK cells, a strict requirement in NK-cell activation.
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http://dx.doi.org/10.15252/emmm.201506164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009809PMC
September 2016

Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair.

Elife 2016 06 15;5. Epub 2016 Jun 15.

Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

Heterogeneity and functional specialization among skin-resident macrophages are incompletely understood. In this study, we describe a novel subset of murine dermal perivascular macrophages that extend protrusions across the endothelial junctions in steady-state and capture blood-borne macromolecules. Unlike other skin-resident macrophages that are reconstituted by bone marrow-derived progenitors after a genotoxic insult, these cells are replenished by an extramedullary radio-resistant and UV-sensitive Bmi1(+) progenitor. Furthermore, they possess a distinctive anti-inflammatory transcriptional profile, which cannot be polarized under inflammatory conditions, and are involved in repair and remodeling functions for which other skin-resident macrophages appear dispensable. Based on all their properties, we define these macrophages as Skin Transendothelial Radio-resistant Anti-inflammatory Macrophages (STREAM) and postulate that their preservation is important for skin homeostasis.
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http://dx.doi.org/10.7554/eLife.15251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961461PMC
June 2016

Targeted Delivery of Immunomodulators to Lymph Nodes.

Cell Rep 2016 05 28;15(6):1202-13. Epub 2016 Apr 28.

Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.
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http://dx.doi.org/10.1016/j.celrep.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973867PMC
May 2016

SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions.

Science 2016 Apr 17;352(6282):242-6. Epub 2016 Mar 17.

Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.

Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169(+) macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans. The CD169(+) macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169(+) macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity.
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http://dx.doi.org/10.1126/science.aaf1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960636PMC
April 2016

Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation.

J Leukoc Biol 2016 08 10;100(2):253-60. Epub 2016 Mar 10.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Harvard-Massachusetts Institute of Technology Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;

Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantation model, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation.
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http://dx.doi.org/10.1189/jlb.1HI0615-248RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945357PMC
August 2016

The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease.

Trends Immunol 2015 Oct;36(10):578-604

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, MA 02139, USA. Electronic address:

The nervous system and the immune system are the principal sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to varied stimuli, and have the capacity to form memories of these encounters leading to learned or 'adaptive' future responses. We review current understanding of the cross-regulation between these systems. The autonomic and somatosensory nervous systems regulate both the development and deployment of immune cells, with broad functions that impact on hematopoiesis as well as on priming, migration, and cytokine production. In turn, specific immune cell subsets contribute to homeostatic neural circuits such as those controlling metabolism, hypertension, and the inflammatory reflex. We examine the contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues and, in this context, discuss opportunities for therapeutic manipulation of neuro-immune interactions.
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http://dx.doi.org/10.1016/j.it.2015.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592743PMC
October 2015

Neutrophil Responses to Sterile Implant Materials.

PLoS One 2015 10;10(9):e0137550. Epub 2015 Sep 10.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States of America; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States of America; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States of America; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States of America; Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, 02115, United States of America.

In vivo implantation of sterile materials and devices results in a foreign body immune response leading to fibrosis of implanted material. Neutrophils, one of the first immune cells to be recruited to implantation sites, have been suggested to contribute to the establishment of the inflammatory microenvironment that initiates the fibrotic response. However, the precise numbers and roles of neutrophils in response to implanted devices remains unclear. Using a mouse model of peritoneal microcapsule implantation, we show 30-500 fold increased neutrophil presence in the peritoneal exudates in response to implants. We demonstrate that these neutrophils secrete increased amounts of a variety of inflammatory cytokines and chemokines. Further, we observe that they participate in the foreign body response through the formation of neutrophil extracellular traps (NETs) on implant surfaces. Our results provide new insight into neutrophil function during a foreign body response to peritoneal implants which has implications for the development of biologically compatible medical devices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565661PMC
May 2016

A Dual Role for Corneal Dendritic Cells in Herpes Simplex Keratitis: Local Suppression of Corneal Damage and Promotion of Systemic Viral Dissemination.

PLoS One 2015 2;10(9):e0137123. Epub 2015 Sep 2.

Schepens Eye Research Institute, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Cornea Service, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

The cornea is the shield to the foreign world and thus, a primary site for peripheral infections. However, transparency and vision are incompatible with inflammation and scarring that may result from infections. Thus, the cornea is required to perform a delicate balance between fighting infections and preserving vision. To date, little is known about the specific role of antigen-presenting cells in viral keratitis. In this study, utilizing an established murine model of primary acute herpes simplex virus (HSV)-1 keratitis, we demonstrate that primary HSV keratitis results in increased conventional dendritic cells (cDCs) and macrophages within 24 hours after infection. Local depletion of cDCs in CD11c-DTR mice by subconjuntival diphtheria toxin injections, led to increased viral proliferation, and influx of inflammatory cells, resulting in increased scarring and clinical keratitis. In addition, while HSV infection resulted in significant corneal nerve destruction, local depletion of cDCs resulted in a much more severe loss of corneal nerves. Further, local cDC depletion resulted in decreased corneal nerve infection, and subsequently decreased and delayed systemic viral transmission in the trigeminal ganglion and draining lymph node, resulting in decreased mortality of mice. In contrast, sham depletion or depletion of macrophages through local injection of clodronate liposomes had neither a significant impact on the cornea, nor an effect on systemic viral transmission. In conclusion, we demonstrate that corneal cDCs may play a primary role in local corneal defense during viral keratitis and preserve vision, at the cost of inducing systemic viral dissemination, leading to increased mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137123PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557979PMC
May 2016