Publications by authors named "Jasmin Herz"

22 Publications

  • Page 1 of 1

Functional characterization of the dural sinuses as a neuroimmune interface.

Cell 2021 Feb 27;184(4):1000-1016.e27. Epub 2021 Jan 27.

Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA; Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.
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http://dx.doi.org/10.1016/j.cell.2020.12.040DOI Listing
February 2021

Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons.

Nat Immunol 2020 11 14;21(11):1421-1429. Epub 2020 Sep 14.

Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.

Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
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http://dx.doi.org/10.1038/s41590-020-0776-4DOI Listing
November 2020

Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance.

J Immunol 2020 01;204(2):286-293

Center for Brain Immunology and Glia, Neuroscience Graduate Program, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908

At steady state, the CNS parenchyma has few to no lymphocytes and less potent Ag-presentation capability compared with other organs. However, the meninges surrounding the CNS host diverse populations of immune cells that influence how CNS-related immune responses develop. Interstitial and cerebrospinal fluid produced in the CNS is continuously drained, and recent advances have emphasized that this process is largely taking place through the lymphatic system. To what extent this fluid process mobilizes CNS-derived Ags toward meningeal immune cells and subsequently the peripheral immune system through the lymphatic vessel network is a question of significant clinical importance for autoimmunity, tumor immunology, and infectious disease. Recent advances in understanding the role of meningeal lymphatics as a communicator between the brain and peripheral immunity are discussed in this review.
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http://dx.doi.org/10.4049/jimmunol.1900838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061974PMC
January 2020

Old T Cells Interfer(on) with Neurogenesis.

Trends Immunol 2019 09 15;40(9):783-785. Epub 2019 Aug 15.

Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Adult neurogenesis plays an important role in brain function and declines with aging. A recent report demonstrates clonal T cell expansion within neurogenic niches of the aged brain, impairing neurogenesis through IFNγ signaling (Dulken et al.,Nature, 2019). These results highlight T cells as important contributors to and potential therapeutic targets for age-related brain dysfunction.
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http://dx.doi.org/10.1016/j.it.2019.07.007DOI Listing
September 2019

Laboratory mice born to wild mice have natural microbiota and model human immune responses.

Science 2019 08 1;365(6452). Epub 2019 Aug 1.

Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.

Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating "wildlings." These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.
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http://dx.doi.org/10.1126/science.aaw4361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377314PMC
August 2019

Morphological and Functional Analysis of CNS-Associated Lymphatics.

Methods Mol Biol 2018 ;1846:141-151

Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA.

The study of meningeal lymphatic vessels of the central nervous system (CNS) has recently gathered momentum, with several papers dissecting their role in draining solutes from cerebrospinal fluid and brain (Louveau et al., Nature 523(7560):337-341, 2015; Antila et al., J Exp Med 214(12):3645-3667, 2017; Aspelund et al., J Exp Med 212(7):991-999, 2015). Methodological capabilities, however, have been limited to few laboratories due to difficulties reproducibly visualizing these rare cell subsets in the meninges. To explore meningeal lymphatics fundamental role during homeostasis and how they may contribute to human pathology, the field has begun to require purification and characterization of lymphatic endothelial cells. Here, modern cell biological techniques involving a combination of histological, flow-cytometric, and functional drainage assays are applied to brain and spinal cord meninges and detailed stepwise procedures used for successful in vivo and ex vivo characterization of meningeal lymphatic vessels.
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http://dx.doi.org/10.1007/978-1-4939-8712-2_9DOI Listing
May 2019

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.

Nat Neurosci 2018 10 17;21(10):1380-1391. Epub 2018 Sep 17.

Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.

Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
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http://dx.doi.org/10.1038/s41593-018-0227-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214619PMC
October 2018

Myeloid Cells in the Central Nervous System.

Immunity 2017 06;46(6):943-956

Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience and Immunotherapy, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany. Electronic address:

The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions.
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http://dx.doi.org/10.1016/j.immuni.2017.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657250PMC
June 2017

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.

JCI Insight 2017 01 26;2(2):e88257. Epub 2017 Jan 26.

Center for Brain Immunology and Glia.

Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in -null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.
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http://dx.doi.org/10.1172/jci.insight.88257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256138PMC
January 2017

Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system.

Nat Microbiol 2016 Feb 15;1:16001. Epub 2016 Feb 15.

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.

An important function of the blood-brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood-brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system.
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http://dx.doi.org/10.1038/nmicrobiol.2016.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966557PMC
February 2016

Bugs and Brain: How Infection Makes You Feel Blue.

Immunity 2016 Apr;44(4):718-20

Center for Brain Immunology and Glia (BIG), Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

In this issue of Immunity, Prinz and colleagues (2016) describe an unexpected mechanism underlying the role of type I interferon in the initiation of cognitive impairment and sickness behavior during viral infection through induction of chemokine CXCL10 in central nervous system epithelial and endothelial cells.
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http://dx.doi.org/10.1016/j.immuni.2016.03.010DOI Listing
April 2016

Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells.

J Exp Med 2015 Jul 29;212(8):1153-69. Epub 2015 Jun 29.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, among others. In contrast, clearance of neurotropic infections is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood-brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain-resident myeloid cells (microglia) by inducing proliferation and converting them into CD11c(+) antigen-presenting cells (APCs). Two-photon imaging experiments revealed that antiviral CD8(+) and CD4(+) T cells interacted directly with CD11c(+) microglia and induced STAT1 signaling but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia.
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http://dx.doi.org/10.1084/jem.20142047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516789PMC
July 2015

c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8(+) memory T-cell survival.

Eur J Immunol 2015 Sep 7;45(9):2672-82. Epub 2015 Jul 7.

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Cellular inhibitor of apoptosis proteins (c-IAP) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of T cells to costimulation. 4-1BB is a TNF receptor family member that signals via a complex that includes TRAF family members and the c-IAPs to upregulate NF-κB and ERK, and has been implicated in memory T-cell survival. Here, we show that effector and memory T cells from mice expressing a dominant negative E3-inactive c-IAP2 (c-IAP2(H570A)) have impaired signaling downstream of 4-1BB. When infected with lymphocytic choriomeningitis virus, unlike mice in which c-IAPs were acutely downregulated by c-IAP antagonists, the primary response of c-IAP2(H570A) mice was normal. However, the number of antigen-specific CD8(+) but not CD4(+) T cells declined more rapidly and to a greater extent in c-IAP2(H570A) mice than in WT controls. Studies with T-cell adoptive transfer demonstrated that the enhanced decay of memory cells was T-cell intrinsic. Thus, c-IAP E3 activity is required for 4-1BB coreceptor signaling and maintenance of CD8(+) T-cell memory.
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http://dx.doi.org/10.1002/eji.201445342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562866PMC
September 2015

TCR ITAM multiplicity is required for the generation of follicular helper T-cells.

Nat Commun 2015 May 11;6:6982. Epub 2015 May 11.

Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Room 2B-210, Building 6B, Bethesda, Maryland 20892, USA.

The T-cell antigen receptor (TCR) complex contains 10 copies of a di-tyrosine Immunoreceptor-Tyrosine-based-Activation-Motif (ITAM) that initiates TCR signalling by recruiting protein tyrosine kinases. ITAM multiplicity amplifies TCR signals, but the importance of this capability for T-cell responses remains undefined. Most TCR ITAMs (6 of 10) are contributed by the CD3ζ subunits. We generated 'knock-in' mice that express non-signalling CD3ζ chains in lieu of wild-type CD3ζ. Here we demonstrate that ITAM multiplicity is important for the development of innate-like T-cells and follicular helper T-cells, events that are known to require strong/sustained TCR-ligand interactions, but is not essential for 'general' T-cell responses including proliferation and cytokine production or for the generation of a diverse antigen-reactive TCR repertoire.
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http://dx.doi.org/10.1038/ncomms7982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428620PMC
May 2015

Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects.

J Neuroinflammation 2015 Apr 29;12:82. Epub 2015 Apr 29.

Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003, Lisbon, Portugal.

Background: The inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS).

Methods: Systemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1(gfp/+) mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.

Results: LPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP(+) cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1(+) cells) were also observed. These changes preceded the migration/proliferation of CX3CR1(+) cells around the vessels at later time points and the subsequent loss of GFAP(+) astrocytes.

Conclusion: Collectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.
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http://dx.doi.org/10.1186/s12974-015-0299-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440597PMC
April 2015

PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis.

J Exp Med 2013 Apr 25;210(4):757-74. Epub 2013 Mar 25.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Immune responses to persistent viral infections and cancer often fail because of intense regulation of antigen-specific T cells-a process referred to as immune exhaustion. The mechanisms that underlie the induction of exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined the dynamics of virus-specific CD8(+) and CD4(+) T cells in the living spleen by two-photon microscopy (TPM) during the establishment of an acute or persistent viral infection. We demonstrate that immune exhaustion during viral persistence maps anatomically to the splenic marginal zone/red pulp and is defined by prolonged motility paralysis of virus-specific CD8(+) and CD4(+) T cells. Unexpectedly, therapeutic blockade of PD-1-PD-L1 restored CD8(+) T cell motility within 30 min, despite the presence of high viral loads. This result was supported by planar bilayer data showing that PD-L1 localizes to the central supramolecular activation cluster, decreases antiviral CD8(+) T cell motility, and promotes stable immunological synapse formation. Restoration of T cell motility in vivo was followed by recovery of cell signaling and effector functions, which gave rise to a fatal disease mediated by IFN-γ. We conclude that motility paralysis is a manifestation of immune exhaustion induced by PD-1 that prevents antiviral CD8(+) T cells from performing their effector functions and subjects them to prolonged states of negative immune regulation.
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http://dx.doi.org/10.1084/jem.20121416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620347PMC
April 2013

Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node.

Immunity 2013 Mar 24;38(3):502-13. Epub 2013 Jan 24.

Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. Here we show that within lymph nodes (LNs), memory CD8+ T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen after antigen recognition. These data reveal the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense.
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http://dx.doi.org/10.1016/j.immuni.2012.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793246PMC
March 2013

Two-photon imaging of microbial immunity in living tissues.

Microsc Microanal 2012 Aug;18(4):730-41

National Institute of Neurological Disorders and Stroke, The National Institutes of Health, Bethesda, MD 20892, USA.

The immune system is highly evolved and can respond to infection throughout the body. Pathogenspecific immune cells are usually generated in secondary lymphoid tissues (e.g., spleen, lymph nodes) and then migrate to sites of infection where their functionality is shaped by the local milieu. Because immune cells are so heavily influenced by the infected tissue in which they reside, it is important that their interactions and dynamics be studied in vivo. Two-photon microscopy is a powerful approach to study host-immune interactions in living tissues, and recent technical advances in the field have enabled researchers to capture movies of immune cells and infectious agents operating in real time. These studies have shed light on pathogen entry and spread through intact tissues as well as the mechanisms by which innate and adaptive immune cells participate in thwarting infections. This review focuses on how two-photon microscopy can be used to study tissue-specific immune responses in vivo, and how this approach has advanced our understanding of host-immune interactions following infection.
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http://dx.doi.org/10.1017/S1431927612000281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771356PMC
August 2012

Migration of cytotoxic lymphocytes in cell cycle permits local MHC I-dependent control of division at sites of viral infection.

J Exp Med 2011 Apr 4;208(4):747-59. Epub 2011 Apr 4.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

After virus infection, cytotoxic T lymphocytes (CTLs) divide rapidly to eradicate the pathogen and prevent the establishment of persistence. The magnitude of an antiviral CTL response is thought to be controlled by the initiation of a cell cycle program within lymphoid tissues. However, it is presently not known whether this division program proceeds during migration or is influenced locally at sites of viral infection. We demonstrate that antiviral CTLs remain in cell cycle while transiting to infected tissues. Up to one third of virus-specific CTLs within blood were found to be in cell cycle after infection with lymphocytic choriomeningitis virus or vesicular stomatitis virus. Using two-photon microscopy, we found that effector CTL divided rapidly upon arrest in the virus-infected central nervous system as well as in meningeal blood vessels. We also observed that MHC I-dependent interactions, but not costimulation, influenced the division program by advancing effector CTL through stages of the cell cycle. These results demonstrate that CTLs are poised to divide in transit and that their numbers can be influenced locally at the site of infection through interactions with cells displaying cognate antigen.
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http://dx.doi.org/10.1084/jem.20101295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135345PMC
April 2011

Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes.

Nat Immunol 2009 Jul 14;10(7):761-8. Epub 2009 Jun 14.

Institute for Medical Microbiology, Immunology and Hygiene, Medical Center, University of Cologne, Germany.

Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8+ T cells. We report that CD8+ T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8+ T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8+ T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8+ T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8+ T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.
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http://dx.doi.org/10.1038/ni.1757DOI Listing
July 2009

Acid sphingomyelinase is required for efficient phago-lysosomal fusion.

Cell Microbiol 2008 Sep 13;10(9):1839-53. Epub 2008 May 13.

Institute for Medical Microbiology, Immunology and Hygiene, Medical Centre of the University of Cologne, Cologne, Germany.

The acid sphingomyelinase (ASMase) localizes to the lumen of endosomes, phagosomes and lysosomes as well as to the outer leaflet of the plasma membrane and hydrolyses sphingomyelin to ceramide and phosphorylcholine. Using the facultative intracellular bacterium Listeria monocytogenes, we show that maturation of phagosomes into phagolysosomes is severely impaired in macrophages genetically deficient for ASMase. Unlike in wild-type macrophages, phagosomes containing L. monocytogenes in ASMase(-/-) macrophages remained positive for the late phagosomal markers mannose-6-phosphate receptor (M6PR) and Rab7 for at least 2 h and, correspondingly, showed delayed acquisition of lysosomal markers like lysosome associated membrane protein 1 (Lamp1). The transfer of lysosomal fluid phase markers into phagosomes containing L. monocytogenes was severely impaired in ASMase(-/-) macrophages and decreased with increasing size of the cargo. Moreover, phagosomes containing L. monocytogenes from ASMase(-/-) cells acquired significantly less listeriocidal proteases cathepsin D, B and L. The results of this study suggest that ASMase is required for the proper fusion of late phagosomes with lysosomes, which is crucial for efficient transfer of lysosomal antibacterial hydrolases into phagosomes.
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http://dx.doi.org/10.1111/j.1462-5822.2008.01169.xDOI Listing
September 2008

Fusogenicity of membranes: the impact of acid sphingomyelinase on innate immune responses.

Immunobiology 2008 31;213(3-4):307-14. Epub 2007 Dec 31.

Institute for Medical Microbiology, Immunology and Hygiene, Medical Center, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany.

Acid sphingomyelinase (ASMase) has been implemented in cellular signaling mainly because its reaction product, ceramide, has been assumed to be a mediator within signaling pathways. Our studies of three independent infection systems show that ASMase is required for phago-lysosomal fusion in macrophages infected with Listeria monocytogenes, for exocytosis of secretory lysosomes by lymphocytic choriomeningitis virus-specific cytotoxic T cells, and for generation of multinucleated giant cells in granuloma of mice infected with Mycobacterium avium. Because of its neutral lipid nature, ceramide is confined to the membranes of phagosomes and lysosomes or the extracellular leaflet of the plasma membrane. In light of the biochemical and biophysical properties of ceramide, we provide a model suggesting that ASMase regulates select vesicular fusion processes by modifying the steric conformation of cellular membranes.
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http://dx.doi.org/10.1016/j.imbio.2007.10.016DOI Listing
July 2008