Publications by authors named "Federica Sallusto"

172 Publications

Risk assessment and seroprevalence of SARS-CoV-2 infection in healthcare workers of COVID-19 and non-COVID-19 hospitals in Southern Switzerland.

Lancet Reg Health Eur 2021 Feb 17;1:100013. Epub 2020 Dec 17.

Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.

Background: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population.

Methods: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions.

Findings: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9-16.5)) compared to other hospital areas at medium (10.7% (7.6-14.6)) or low risk exposure (7.3% (6.4-8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91-2.22),  = 0.119, and 1.98 (1.55-2.53), <0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0-11.3)) compared to other employees at medium (7.1% (4.8-10.0)) or low risk exposure (6.6% (5.0-8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89-2.11),  = 0.149, and 1.75 (1.28-2.40),  = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3-22.5) vs. 7.7% (6.9-8.6), OR 2.80 (2.14-3.67), <0.001).

Interpretation: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at reducing nosocomial viral transmission are effective. Household contact with known COVID-19 cases represents the highest risk of seropositivity.

Funding: Henry Krenter Foundation, Ente Ospedaliero Cantonale and Vir Biotechnology.
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http://dx.doi.org/10.1016/j.lanepe.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833818PMC
February 2021

High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency.

J Exp Med 2021 Aug 23;218(8). Epub 2021 Jun 23.

Institute of Microbiology, Eidgenössische Technische Hochschule Zurich, Zurich, Switzerland.

We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri-immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient's CD4+ αβ T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αβ T lymphocytes.
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http://dx.doi.org/10.1084/jem.20202726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225679PMC
August 2021

Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2.

Science 2021 06 18;372(6548):1336-1341. Epub 2021 May 18.

Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.

The identification of CD4 T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19-recovered individuals a robust CD4 T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346-S365 region comprising nested human leukocyte antigen DR (HLA-DR)- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.
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http://dx.doi.org/10.1126/science.abg8985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168615PMC
June 2021

The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study.

J Sleep Res 2021 Apr 4:e13296. Epub 2021 Apr 4.

Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH.
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http://dx.doi.org/10.1111/jsr.13296DOI Listing
April 2021

Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.

Nature 2021 Apr 31;592(7855):639-643. Epub 2021 Mar 31.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.
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http://dx.doi.org/10.1038/s41586-021-03378-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068667PMC
April 2021

Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature.

Acta Neuropathol 2021 06 28;141(6):901-915. Epub 2021 Mar 28.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature Th and Th cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.
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http://dx.doi.org/10.1007/s00401-021-02299-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113175PMC
June 2021

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

Cell 2021 03 28;184(5):1171-1187.e20. Epub 2021 Jan 28.

MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK.

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.cell.2021.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843029PMC
March 2021

Rationally designed Human Cytomegalovirus gB nanoparticle vaccine with improved immunogenicity.

PLoS Pathog 2020 12 28;16(12):e1009169. Epub 2020 Dec 28.

Institute for Research in Biomedicine, Università della Svizzera italiana, faculty of Biomedical Sciences, Bellinzona, Switzerland.

Human cytomegalovirus (HCMV) is the primary viral cause of congenital birth defects and causes significant morbidity and mortality in immune-suppressed transplant recipients. Despite considerable efforts in vaccine development, HCMV infection still represents an unmet clinical need. In recent phase II trials, a MF59-adjuvanted gB vaccine showed only modest efficacy in preventing infection. These findings might be attributed to low level of antibodies (Abs) with a neutralizing activity induced by this vaccine. Here, we analyzed the immunogenicity of each gB antigenic domain (AD) and demonstrated that domain I of gB (AD5) is the main target of HCMV neutralizing antibodies. Furthermore, we designed, characterized and evaluated immunogenic responses to two different nanoparticles displaying a trimeric AD5 antigen. We showed that mice immunization with nanoparticles induces sera neutralization titers up to 100-fold higher compared to those obtained with the gB extracellular domain (gBECD). Collectively, these results illustrate with a medically relevant example the advantages of using a general approach combining antigen discovery, protein engineering and scaffold presentation for modern development of subunit vaccines against complex pathogens.
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http://dx.doi.org/10.1371/journal.ppat.1009169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794029PMC
December 2020

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 12 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France.

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

Broadly reactive human CD4 T cells against Enterobacteriaceae are found in the naïve repertoire and are clonally expanded in the memory repertoire.

Eur J Immunol 2021 Mar 28;51(3):648-661. Epub 2020 Dec 28.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

Enterobacteriaceae are a large family of Gram-negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks of multi-antibiotics resistant strains, thus being a major public health threat. In this study, we report that Enterobacteriaceae-reactive memory Th cells were highly enriched in a CCR6 CXCR3 Th1*/17 cell subset and produced IFN-γ, IL-17A, and IL-22. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumonie-reactive T cells. By combining heterologous antigenic stimulation, single cell cloning and TCR Vβ sequencing, we demonstrate that a large fraction of memory Th cell clones was broadly cross-reactive to several Enterobacteriaceae species. These cross-reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A antigen. Interestingly, Enterobacteriaceae broadly cross-reactive T cells were also prominent among in vitro primed naïve T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted by cross-reactive T cells that are readily found in the pre-immune repertoire and are clonally expanded in the memory repertoire.
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http://dx.doi.org/10.1002/eji.202048630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986685PMC
March 2021

Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Cell 2020 11 16;183(4):1024-1042.e21. Epub 2020 Sep 16.

III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.
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http://dx.doi.org/10.1016/j.cell.2020.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494283PMC
November 2020

Deciphering and predicting CD4+ T cell immunodominance of influenza virus hemagglutinin.

J Exp Med 2020 10;217(10)

Institute for Research in Biomedicine, Università della Svizzera italiana, Faculty of Biomedical Sciences, Bellinzona, Switzerland.

The importance of CD4+ T helper (Th) cells is well appreciated in view of their essential role in the elicitation of antibody and cytotoxic T cell responses. However, the mechanisms that determine the selection of immunodominant epitopes within complex protein antigens remain elusive. Here, we used ex vivo stimulation of memory T cells and screening of naive and memory T cell libraries, combined with T cell cloning and TCR sequencing, to dissect the human naive and memory CD4+ T cell repertoire against the influenza pandemic H1 hemagglutinin (H1-HA). We found that naive CD4+ T cells have a broad repertoire, being able to recognize naturally processed as well as cryptic peptides spanning the whole H1-HA sequence. In contrast, memory Th cells were primarily directed against just a few immunodominant peptides that were readily detected by mass spectrometry-based MHC-II peptidomics and predicted by structural accessibility analysis. Collectively, these findings reveal the presence of a broad repertoire of naive T cells specific for cryptic H1-HA peptides and demonstrate that antigen processing represents a major constraint determining immunodominance.
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http://dx.doi.org/10.1084/jem.20200206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537397PMC
October 2020

Dynamics in protein translation sustaining T cell preparedness.

Nat Immunol 2020 08 6;21(8):927-937. Epub 2020 Jul 6.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells ( https://www.immunomics.ch ).
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http://dx.doi.org/10.1038/s41590-020-0714-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610365PMC
August 2020

Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α-dependent pathways.

Proc Natl Acad Sci U S A 2020 06 14;117(22):12269-12280. Epub 2020 May 14.

Cellular Immunology Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on and (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.
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http://dx.doi.org/10.1073/pnas.1918196117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275751PMC
June 2020

Human CD4 T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro.

Fluids Barriers CNS 2020 Feb 3;17(1). Epub 2020 Feb 3.

Theodor Kocher Institute, University of Bern, Bern, Switzerland.

Background: The brain barriers establish compartments in the central nervous system (CNS) that significantly differ in their communication with the peripheral immune system. In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood-brain barrier (BBB) or the epithelial blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP).

Objective: Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4 T-cell subsets across the BBB versus the BCSFB.

Methods: Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4 T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro.

Results: While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10- to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barrier-crossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration.

Conclusions: Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB.
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http://dx.doi.org/10.1186/s12987-019-0165-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996191PMC
February 2020

Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis.

Front Immunol 2019 14;10:3056. Epub 2020 Jan 14.

Theodor Kocher Institute, University of Bern, Bern, Switzerland.

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), myelin-specific T cells are activated in the periphery and differentiate in T helper (Th) 1 and Th17 effector cells, which cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), where they induce neuroinflammation. Here, we explored the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in the activation of naïve myelin-specific T cells and in the subsequent migration of differentiated encephalitogenic Th1 and Th17 cells across the BBB and . While on antigen-presenting cells ICAM-1, but not ICAM-2 was required for the activation of naïve CD4 T cells, endothelial ICAM-1 and ICAM-2 mediated both Th1 and Th17 cell migration across the BBB. ICAM-1/-2-deficient mice developed ameliorated typical and atypical EAE transferred by encephalitogenic Th1 and Th17 cells, respectively. Our study underscores important yet cell-specific contributions for ICAM-1 and ICAM-2 in EAE pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2019.03056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970977PMC
November 2020

CXCR3 Identifies Human Naive CD8 T Cells with Enhanced Effector Differentiation Potential.

J Immunol 2019 12 18;203(12):3179-3189. Epub 2019 Nov 18.

Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy;

In mice, the ability of naive T (T) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8 T cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3 T cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3 T cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3 T cells were transcriptionally equivalent to murine CXCR3 T cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8 T cells.
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http://dx.doi.org/10.4049/jimmunol.1901072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900484PMC
December 2019

Editorial overview: Overview of the articles - special section on human immunology.

Curr Opin Immunol 2019 08;59:vi

Institute for Research in Biomedicine, Università della Svizzera italiana, Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland; ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.coi.2019.09.001DOI Listing
August 2019

The challenges of primary biliary cholangitis: What is new and what needs to be done.

J Autoimmun 2019 12 20;105:102328. Epub 2019 Sep 20.

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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http://dx.doi.org/10.1016/j.jaut.2019.102328DOI Listing
December 2019

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients.

Nat Med 2019 09 9;25(9):1402-1407. Epub 2019 Sep 9.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS), but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4 T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.
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http://dx.doi.org/10.1038/s41591-019-0568-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795539PMC
September 2019

Frequency determination of breast tumor-reactive CD4 and CD8 T cells in humans: unveiling the antitumor immune response.

Oncoimmunology 2019;8(8):1607674. Epub 2019 May 15.

Department of Immunology, Institute of Biomedical Sciences of the University of Sao Paulo, Sao Paulo, Brazil.

As cancer immunotherapy gains importance, the determination of a patient's ability to react to his/her tumor is unquestionably relevant. Though the presence of T cells that recognize specific tumor antigens is well established, the total frequency of tumor-reactive T cells in humans is difficult to assess, especially due to the lack of broad analysis techniques. Here, we describe a strategy that allows this determination, in both CD4 and CD8 compartments, using T cell proliferation induced by tumor cell-lysate pulsed dendritic cells as the readout. All 12 healthy donor tested had circulating CD4 and CD8 tumor cell-reactive T cells. The detection of these T cells, not only in the naïve but also in the memory compartment, can be seen as an evidence of tumor immunosurveillance in humans. As expected, breast cancer patients had higher frequencies of blood tumor-reactive T cells, but with differences among breast cancer subtypes. Interestingly, the frequency of blood tumor-reactive T cells in patients did not correlate to the frequency of infiltrating tumor-reactive T cells, highlighting the danger of implying a local tumor response from blood obtained data. In conclusion, these data add T cell evidence to immunosurveillance in humans, confirm that immune parameters in blood may be misleading and describe a tool to follow the tumor-specific immune response in patients and, thus, to design better immunotherapeutic approaches.
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http://dx.doi.org/10.1080/2162402X.2019.1607674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682358PMC
May 2019

Protection against influenza infection requires early recognition by inflammatory dendritic cells through C-type lectin receptor SIGN-R1.

Nat Microbiol 2019 11 29;4(11):1930-1940. Epub 2019 Jul 29.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

The early phase of influenza infection occurs in the upper respiratory tract and the trachea, but little is known about the initial events of virus recognition and control of viral dissemination by the immune system. Here, we report that inflammatory dendritic cells (IDCs) are recruited to the trachea shortly after influenza infection through type I interferon-mediated production of the chemokine CCL2. We further show that recruited IDCs express the C-type lectin receptor SIGN-R1, which mediates direct recognition of the virus by interacting with N-linked glycans present in glycoproteins of the virion envelope. Activation of IDCs via SIGN-R1 triggers the production of the chemokines CCL5, CXCL9 and CXCL10, which initiate the recruitment of protective natural killer (NK) cells in the infected trachea. In the absence of SIGN-R1, the recruitment and activation of NK cells is impaired, leading to uncontrolled viral proliferation. In sum, our results provide insight into the orchestration of the early cellular and molecular events involved in immune protection against influenza.
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http://dx.doi.org/10.1038/s41564-019-0506-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817362PMC
November 2019

Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment.

Nat Rev Neurol 2019 09 19;15(9):519-539. Epub 2019 Jul 19.

Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France.

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.
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http://dx.doi.org/10.1038/s41582-019-0226-9DOI Listing
September 2019

PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation.

Front Immunol 2019 5;10:711. Epub 2019 Apr 5.

Theodor Kocher Institute, University of Bern, Bern, Switzerland.

Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical gray matter MS lesions. Using a human BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4 T-cell subsets (Th1, Th1, Th2, and Th17) across the BBB. Employing an additional BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization, and crawling of effector/memory CD4 T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance.
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http://dx.doi.org/10.3389/fimmu.2019.00711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460670PMC
September 2020

The Skin Commensal Yeast Malassezia Triggers a Type 17 Response that Coordinates Anti-fungal Immunity and Exacerbates Skin Inflammation.

Cell Host Microbe 2019 Mar;25(3):389-403.e6

Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich 8057, Switzerland. Electronic address:

Commensal fungi of the mammalian skin, such as those of the genus Malassezia, are associated with atopic dermatitis and other common inflammatory skin disorders. Understanding of the causative relationship between fungal commensalism and disease manifestation remains incomplete. By developing a murine epicutaneous infection model, we found Malassezia spp. selectively induce IL-17 and related cytokines. This response is key in preventing fungal overgrowth on the skin, as disruption of the IL-23-IL-17 axis compromises Malassezia-specific cutaneous immunity. Under conditions of impaired skin integrity, mimicking a hallmark of atopic dermatitis, the presence of Malassezia dramatically aggravates cutaneous inflammation, which again was IL-23 and IL-17 dependent. Consistently, we found a CCR6 Th17 subset of memory T cells to be Malassezia specific in both healthy individuals and atopic dermatitis patients, whereby the latter showed enhanced frequency of these cells. Thus, the Malassezia-induced type 17 response is pivotal in orchestrating antifungal immunity and in actively promoting skin inflammation.
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http://dx.doi.org/10.1016/j.chom.2019.02.002DOI Listing
March 2019

Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus.

Cell 2019 03;176(6):1420-1431.e17

Department of Biochemistry, University of Washington, Seattle, WA, USA; Institute for Protein Design, University of Washington, Seattle, WA, USA. Electronic address:

Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.
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http://dx.doi.org/10.1016/j.cell.2019.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424820PMC
March 2019

Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner.

Cell Rep 2019 02;26(9):2307-2315.e5

Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. Electronic address:

The role of natural killer (NK) cells in the immune response against vaccines is not fully understood. Here, we examine the function of infiltrated NK cells in the initiation of the inflammatory response triggered by inactivated influenza virus vaccine in the draining lymph node (LN). We observed that, following vaccination, NK cells are recruited to the interfollicular and medullary areas of the LN and become activated by type I interferons (IFNs) produced by LN macrophages. The activation of NK cells leads to their early production of IFNγ, which in turn regulates the recruitment of IL-6+ CD11b+ dendritic cells. Finally, we demonstrate that the interleukin-6 (IL-6)-mediated inflammation is important for the development of an effective humoral response against influenza virus in the draining LN.
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http://dx.doi.org/10.1016/j.celrep.2019.01.104DOI Listing
February 2019

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23.

Sci Immunol 2018 12;3(30)

Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 T cells, including, in particular, mycobacterium-specific T1* cells (CD45RACCR6), is dependent on both IL-12 and IL-23. Last, we show that , , and have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.
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http://dx.doi.org/10.1126/sciimmunol.aau6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380365PMC
December 2018

A silicon nanomembrane platform for the visualization of immune cell trafficking across the human blood-brain barrier under flow.

J Cereb Blood Flow Metab 2019 03 19;39(3):395-410. Epub 2018 Dec 19.

1 Theodor Kocher Institute, University of Bern, Bern, Switzerland.

Here we report on the development of a breakthrough microfluidic human in vitro cerebrovascular barrier (CVB) model featuring stem cell-derived brain-like endothelial cells (BLECs) and nanoporous silicon nitride (NPN) membranes (µSiM-CVB). The nanoscale thinness of NPN membranes combined with their high permeability and optical transparency makes them an ideal scaffold for the assembly of an in vitro microfluidic model of the blood-brain barrier (BBB) featuring cellular elements of the neurovascular unit (NVU). Dual-chamber devices divided by NPN membranes yield tight barrier properties in BLECs and allow an abluminal pericyte-co-culture to be replaced with pericyte-conditioned media. With the benefit of physiological flow and superior imaging quality, the µSiM-CVB platform captures each phase of the multi-step T-cell migration across the BBB in live cell imaging. The small volume of <100 µL of the µSiM-CVB will enable in vitro investigations of rare patient-derived immune cells with the human BBB. The µSiM-CVB is a breakthrough in vitro human BBB model to enable live and high-quality imaging of human immune cell interactions with the BBB under physiological flow. We expect it to become a valuable new tool for the study of cerebrovascular pathologies ranging from neuroinflammation to metastatic cancer.
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http://dx.doi.org/10.1177/0271678X18820584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421249PMC
March 2019

Publisher Correction: An immunoregulatory and tissue-residency program modulated by c-MAF in human T17 cells.

Nat Immunol 2019 01;20(1):109

Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.

In the version of this article initially published, in the legend to Fig. 1b, the description of the frequency of T17-IL-10 clones was incomplete for the first group; this should read as follows: "...13 experiments with clones isolated from CCR6CCR4CXCR3 T cells...". Also, the label along the vertical axis of the bottom right plot in Figure 5b was incomplete; the correct label is 'IFN-γ cells (%)'. Finally, in the first sentence of the final paragraph of the final Results subsection, the description of the regions analyzed was incorrect; that sentence should begin: "DNA motif-enrichment analysis of the subset-specific H3K27ac-positive regions...". The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-018-0264-2DOI Listing
January 2019