Publications by authors named "Nir Yogev"

33 Publications

IL-17 controls central nervous system autoimmunity through the intestinal microbiome.

Sci Immunol 2021 Feb;6(56)

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4 T helper cells (T17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.aaz6563DOI Listing
February 2021

A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis.

Science 2021 01;371(6525):145-153

TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Freiligrathstr. 12, Mainz 55131, Germany.

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (T cell) populations. Notably, these T cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.
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http://dx.doi.org/10.1126/science.aay3638DOI Listing
January 2021

Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation.

Front Immunol 2020 16;11:614509. Epub 2020 Dec 16.

Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [] confirms that LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
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http://dx.doi.org/10.3389/fimmu.2020.614509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772211PMC
December 2020

Induction of Regulatory T Cells in Leishmania major‒Infected BALB/c Mice Does Not Require Langerin+ Dendritic Cells.

J Invest Dermatol 2021 Apr 14;141(4):936-938. Epub 2020 Sep 14.

Department of Dermatology, Faculty of Medicine, University of Cologne, Cologne, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.04.033DOI Listing
April 2021

IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants.

J Allergy Clin Immunol 2020 09 21;146(3):652-666.e11. Epub 2020 May 21.

Laboratories of Immunology and Antibody Glycan Analysis, Institute for Nutritional Medicine, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, Germany; Laboratory of Tolerance and Autoimmunity at the German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany; Airway Research Center North, University of Lübeck, German Center for Lung Research, Lübeck, Germany. Electronic address:

Background: Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.

Objective: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants.

Methods: Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns.

Results: Different adjuvants induce distinct IgG GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3 follicular helper T (T) cell-inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor-dependent IFN-γ T cells, IL-6/IL-23-dependent IL-17A T cells, and high ratios of T cells to Foxp3 follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor.

Conclusion: This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.
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http://dx.doi.org/10.1016/j.jaci.2020.04.059DOI Listing
September 2020

Estrogen Signaling in Bystander Foxp3 CD4 T Cells Suppresses Cognate Th17 Differentiation in and Protects from Central Nervous System Autoimmunity.

J Immunol 2018 12 24;201(11):3218-3228. Epub 2018 Oct 24.

Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, INSERM, CNRS, Université Paul Sabatier, 31300 Toulouse, France;

17β-Estradiol (E2) suppresses the development of experimental autoimmune encephalomyelitis (EAE) through estrogen receptor (ER) α, yet the cellular targets remain elusive. We have used an adoptive transfer model of myelin oligodendrocyte glycoprotein-specific CD4 T cells from 2D2 TCR transgenic mice. We show that in the recipient mice, ERα expression in bystander CD4 T cells, rather than in cognate 2D2 T cells, is required for the inhibition of Th17 cell differentiation by E2. Coadministration of estrogen-primed WT, but not ERα-deficient CD4 T cells, with naive 2D2 T cells lacking ERα inhibited the development of Th17 cell-mediated EAE. Suppression of Th17 cells and protection from EAE were maintained when ERα was deleted in Foxp3 regulatory T cells. We showed that in vivo PD-L1 blockade alleviated the anti-inflammatory action of E2 and that PD-1 expression on cognate but not bystander T cells was required for the E2-dependent inhibition of Th17 differentiation. In cotransfer experiments, we found that only WT but not PD-1 2D2 T cells were amenable to E2-dependent inhibition of Th17 differentiation. These results support the conclusion that the restriction of Th17 cell development by E2-primed bystander CD4 T cells requires cell-intrinsic PD-1 signaling within cognate T cells rather than induction of regulatory 2D2 T cells through PD-1 engagement. Altogether, our results indicate that pregnancy-level concentrations of estrogen signal in conventional Foxp3 CD4 T cells to limit the differentiation of cognate Th17 cells through a -acting mechanism of suppression that requires a functional PD-1/PD-L1 regulatory axis.
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http://dx.doi.org/10.4049/jimmunol.1800417DOI Listing
December 2018

Inhibition of experimental autoimmune encephalomyelitis by tolerance-promoting DNA vaccination focused to dendritic cells.

PLoS One 2018 6;13(2):e0191927. Epub 2018 Feb 6.

Department of Dermatology University Medical Center, Mainz, Germany.

In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG). For comparison, the strong and ubiquitously active CMV promoter was employed (pCMV-MOG), which allows MOG expression in all transfected cells. Expression of IL-10 and TGF-ß1 was controlled by the CMV promoter to yield maximal synthesis (pCMV-IL10, pCMV-TGFß). Co-application of pFscn-MOG and pCMV-IL10 significantly ameliorated EAE pathology, while vaccination with pCMV-MOG plus pCMV-IL10 did not affect EAE outcome. In contrast, vaccination with either of the two MOG-encoding plasmids in combination with pCMV-TGFß significantly attenuated the clinical EAE symptoms. Mechanistically, we observed diminished infiltration of Th17 and Th1 cells as well as macrophages/DCs into the CNS, which correlated with decreased MOGp35-55-specific production of IL-17 and IFN-ϫ by spleen cells and reduced peptide-specific T cell proliferation. Our findings suggest deletion of or anergy induction in MOG-specific CD4+ T cells by the suppressive vaccination platform employed. MOG expression driven by the DC-specific fascin1 promoter yielded similar inhibitory effects on EAE progression as the ubiquitously active viral CMV promoter, when coapplying pCMV-TGFß. Our finding that pCMV-IL10 promoted tolerogenic effects only, when coapplied with pFscn-MOG, but not pCMV-MOG suggests that IL-10 affected only directly transfected DCs (pFscn-MOG), but not neighbouring DCs that engulfed MOG-containing vesicles derived from transfected keratinocytes (pCMV-MOG). Thus, due to its DC-restricted expression, the fascin1 promoter might be an interesting alternative to ubiquitously expressed promoters for vaccination strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191927PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800700PMC
April 2018

A novel microglial subset plays a key role in myelinogenesis in developing brain.

EMBO J 2017 11 28;36(22):3292-3308. Epub 2017 Sep 28.

Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark

Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation-activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin-like growth factor 1, and its selective depletion from CD11c microglia leads to impairment of primary myelination. CD11c-targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis.
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http://dx.doi.org/10.15252/embj.201696056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686552PMC
November 2017

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

NG2 plays a role in neuroinflammation but is not expressed by immune cells.

Acta Neuropathol 2017 08 31;134(2):325-327. Epub 2017 May 31.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

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http://dx.doi.org/10.1007/s00401-017-1735-5DOI Listing
August 2017

TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity.

Proc Natl Acad Sci U S A 2017 02 6;114(8):E1480-E1489. Epub 2017 Feb 6.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8CD103 DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.
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http://dx.doi.org/10.1073/pnas.1615065114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338403PMC
February 2017

EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells.

Cell Rep 2017 01;18(5):1270-1284

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany. Electronic address:

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.
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http://dx.doi.org/10.1016/j.celrep.2017.01.020DOI Listing
January 2017

Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T17 cells.

Nat Immunol 2017 01 28;18(1):74-85. Epub 2016 Nov 28.

Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T17-cell-mediated autoimmune diseases.
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http://dx.doi.org/10.1038/ni.3632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164931PMC
January 2017

Dendritic cells as gatekeepers of tolerance.

Semin Immunopathol 2017 02 25;39(2):153-163. Epub 2016 Jul 25.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.
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http://dx.doi.org/10.1007/s00281-016-0583-zDOI Listing
February 2017

Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

J Exp Med 2016 Mar 22;213(3):415-31. Epub 2016 Feb 22.

Department of Pathology, New York University Langone Medical Center, New York, NY 10016 Department of Medicine, New York University Langone Medical Center, New York, NY 10016 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032

A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.
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http://dx.doi.org/10.1084/jem.20150642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813676PMC
March 2016

Gatekeeper role of brain antigen-presenting CD11c+ cells in neuroinflammation.

EMBO J 2016 Jan 26;35(1):89-101. Epub 2015 Nov 26.

Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen-presenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c(+) cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c(+) cells. These CD11c(+) cells are organized in perivascular clusters, targeted by T cells, and strongly express the inflammatory chemokines Ccl5, Cxcl9, and Cxcl10. Our findings demonstrate a fundamental role of CNS CD11c(+) cells in the attraction of pathogenic T cells into and their survival within the CNS. Depletion of CD11c(+) cells markedly reduced disease severity due to impaired enrichment of pathogenic T cells within the CNS.
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http://dx.doi.org/10.15252/embj.201591488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718005PMC
January 2016

IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology.

Nat Commun 2015 Mar 12;6:6525. Epub 2015 Mar 12.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

Gut homeostasis and mucosal immune defense rely on the differential contributions of dendritic cells (DC) and macrophages. Here we show that colonic CX3CR1(+) mononuclear phagocytes are critical inducers of the innate response to Citrobacter rodentium infection. Specifically, the absence of IL-23 expression in macrophages or CD11b(+) DC results in the impairment of IL-22 production and in acute lethality. Highlighting immunopathology as a death cause, infected animals are rescued by the neutralization of IL-12 or IFNγ. Moreover, mice are also protected when the CD103(+) CD11b(-) DC compartment is rendered deficient for IL-12 production. We show that IL-12 production by colonic CD103(+) CD11b(-) DC is repressed by IL-23. Collectively, in addition to its role in inducing IL-22 production, macrophage-derived or CD103(-) CD11b(+) DC-derived IL-23 is required to negatively control the otherwise deleterious production of IL-12 by CD103(+) CD11b(-) DC. Impairment of this critical mononuclear phagocyte crosstalk results in the generation of IFNγ-producing former TH17 cells and fatal immunopathology.
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http://dx.doi.org/10.1038/ncomms7525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382688PMC
March 2015

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

Arterioscler Thromb Vasc Biol 2014 Dec 23;34(12):2658-68. Epub 2014 Oct 23.

From the Institute for Molecular Medicine (S.K., A.L.C., R.S., N.Y., A.N., S.R., A.W.), Department of Medicine 2 (S.K., M.O., D.M., M.K., P. Wild, A.D., P. Wenzel, T.M.), Department of Dermatology (J.W., L.K., E.v.S.), Department of Pharmacology (H.L., Z.W.), Institute for Pathology (C.B.), Center for Thrombosis and Hemostasis (P. Wild, P. Wenzel, T.M.), German Center for Cardiovascular Research (DZHK), partner site RhineMain (A.U., P.W.), and Department of Medicine 3 (M.R.), University Medical Center of the Johannes-Gutenberg University of Mainz, Germany; Department of Internal Medicine I, University Hospital Erlangen, Germany (M.W., M.F.N.); Institute of Anatomy, University of Leipzig, Germany (C.P., I.B.); Institute for Biochemistry, Christian-Albrechts-University of Kiel, Germany (S.R.-J.); Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany (J.S.).

Objective: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.

Approach And Results: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice.

Conclusions: Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice.
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http://dx.doi.org/10.1161/ATVBAHA.114.304108DOI Listing
December 2014

Host-derived CD8⁺ dendritic cells protect against acute graft-versus-host disease after experimental allogeneic bone marrow transplantation.

Biol Blood Marrow Transplant 2014 Nov 13;20(11):1696-704. Epub 2014 Aug 13.

IIIrd Department of Medicine, Johannes Gutenberg-University Medical Center, Mainz, Germany. Electronic address:

Graft-versus-host disease (GVHD) is a frequent life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT) and induced by donor-derived T cells that become activated by host antigen-presenting cells. To address the relevance of host dendritic cell (DC) populations in this disease, we used mouse strains deficient in CD11c(+) or CD8α(+) DC populations in a model of acute GVHD where bone marrow and T cells from BALB/c donors were transplanted into C57BL/6 hosts. Surprisingly, a strong increase in GVHD-related mortality was observed in the absence of CD11c(+) cells. Likewise, Batf3-deficient (Batf3(-/-)) mice that lack CD8α(+) DCs also displayed a strongly increased GVHD-related mortality. In the absence of CD8α(+) DCs, we detected an increased activation of the remaining DC populations after HSCT, leading to an enhanced priming of allogeneic T cells. Importantly, this was associated with reduced numbers of regulatory T cells and transforming growth factor-β levels, indicating an aggravated failure of peripheral tolerance mechanisms after HSCT in the absence of CD8α(+) DCs. In summary, our results indicate a critical role of CD8α(+) DCs as important inducers of regulatory T cell-mediated tolerance to control DC activation and T cell priming in the initiation phase of GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2014.08.005DOI Listing
November 2014

Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10.

Proc Natl Acad Sci U S A 2014 Aug 29;111(32):11810-5. Epub 2014 Jul 29.

Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland;

The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by extracts from other enteropathogens and requires a heat-sensitive H. pylori component and the DC-intrinsic production of IL-10. The basic leucine zipper ATF-like 3 (BATF3)-dependent CD103(+)CD11b(-) dendritic cell lineage is enriched in the lungs of protected mice and strictly required for protection. Two H. pylori persistence determinants, the γ-glutamyl-transpeptidase GGT and the vacuolating cytotoxin VacA, are required and sufficient for asthma protection and can be administered in purified form to prevent asthma. In conclusion, we provide preclinical evidence for the concept that the immunomodulatory properties of H. pylori can be exploited for tolerization strategies aiming to prevent allergen-induced asthma.
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http://dx.doi.org/10.1073/pnas.1410579111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136625PMC
August 2014

IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions.

J Invest Dermatol 2014 Mar 25;134(3):728-735. Epub 2013 Sep 25.

Institute for Molecular Medicine, University Medical Center of the Johannes-Gutenberg University of Mainz, Mainz, Germany. Electronic address:

The lack of a generally accepted animal model for human psoriasis has hindered progress with respect to understanding the pathogenesis of the disease. Here we present a model in which transgenic IL-17A expression is targeted to the skin in mice, achievable after crossing our IL-17A(ind) allele to the K14-Cre strain. K14-IL-17A(ind/+) mice invariably develop an overt skin inflammation bearing many hallmark characteristics of human psoriasis including dermal infiltration of effector T cells, formation of neutrophil microabscesses, and hyperkeratosis. IL-17A expression in the skin results in upregulated granulopoiesis and migration of IL-6R-expressing neutrophils into the skin. Neutralization of IL-6 signaling efficiently reduces the observed pathogenesis in skin of IL-17A-overexpressing mice, with marked reductions in epidermal neutrophil abscess formation and epidermal thickening. Thus, IL-6 functions downstream of IL-17A to exacerbate neutrophil microabscess development in psoriasiform lesions.
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http://dx.doi.org/10.1038/jid.2013.404DOI Listing
March 2014

Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis.

Brain 2013 Apr 20;136(Pt 4):1048-66. Epub 2013 Mar 20.

Focus Program Translational Neuroscience, Rhine Main Neuroscience Network, University Medical Centre of the Johannes Gutenberg-University of Mainz, 55131 Mainz, Germany.

Laquinimod is an orally administered compound that is under investigation in relapsing-remitting multiple sclerosis. To understand the mechanism by which laquinimod exerts its clinical effects, we have performed human and murine studies assessing its immunomodulatory properties. In experimental autoimmune encephalomyelitis, the therapeutic administration of laquinimod beginning during the recovery of SJL mice, prevented further relapses as expected and strongly reduced infiltration of CD4+ and CD8+ T cells in the central nervous system. We hypothesized that this beneficial effect was mediated by dendritic cells, since we and others found a modulation of different dendritic cell subsets under treatment. According to the findings on antigen-presenting cells in the murine system, we found a reduced capacity of human monocyte-derived dendritic cells treated with therapeutic concentrations of laquinimod, upon maturation with lipopolysaccharide, to induce CD4+ T cell proliferation and secretion of pro-inflammatory cytokines. Furthermore, laquinimod treatment of mature dendritic cells resulted in a decreased chemokine production by both murine and human dendritic cells, associated with a decreased monocyte chemo-attraction. In laquinimod-treated patients with multiple sclerosis we consistently found reduced chemokine and cytokine secretion by conventional CD1c+ dendritic cells upon lipopolysaccharide stimulation. Similarly to the animal model of relapsing-remitting multiple sclerosis, dendritic cell subsets were altered in patients upon laquinimod treatment, as the number of conventional CD1c+ and plasmacytoid CD303+ dendritic cells were decreased within peripheral blood mononuclear cells. Moreover, laquinimod treatment in patients with multiple sclerosis and mice modified the maturation of dendritic cells demonstrated by an upregulation of CD86 expression in vivo. Our data suggest that inhibition of the NF-κB pathway is responsible for the changes observed in dendritic cell maturation and functions. These findings indicate that laquinimod exhibits its disease-modulating activity in multiple sclerosis by downregulating immunogenicity of dendritic cell responses. We suggest that monitoring dendritic cell properties in multiple sclerosis should be implemented in future therapeutic trials.
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http://dx.doi.org/10.1093/brain/awt023DOI Listing
April 2013

Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance.

J Allergy Clin Immunol 2012 Sep;130(3):781-797.e11

Department of Dermatology, University Medical Center, Johannes Gutenberg-University of Mainz, Mainz, Germany.

Background: Allergic contact dermatitis is one of the most common occupational diseases. A main protective mechanism in those who do not develop allergic contact dermatitis is tolerance induction by repeated exposure to low doses of contact allergen, which is termed low zone tolerance (LZT). The mechanisms that determine the tolerance induction in subjects with LZT are still elusive.

Objective: We performed analysis of the role of CD4(+)CD25(+) forkhead box protein 3 (FOXP3)-positive regulatory T (Treg) cells and dendritic cells (DCs) in mice with LZT.

Methods: Mechanisms of tolerance induction were analyzed in a murine model of LZT by using FOXP3 and IL-10 reporter mice, as well as mice that allow the selective depletion of Treg cells or DCs.

Results: Depletion of CD4(+)CD25(+)FOXP3(+) Treg cells during tolerance induction completely abolishes the development of LZT, resulting in a pronounced contact hypersensitivity response. Adoptive transfer experiments, depletion studies, and use of cell type-specific deficient mice revealed that IL-10 production is critical for the suppressor function of Treg cells in mice with LZT and that tolerogenic CD8(+)CD11c(+) DCs located in the skin-draining lymph nodes are essential for LZT. In the absence of Treg cells, DCs did not develop tolerogenic functions, indicating that activated IL-10(+) Treg cells might imprint the tolerogenic DC phenotype. Cell communication analysis revealed that the education of tolerogenic DCs might involve a direct interaction with Treg cells mediated by gap junctions. Subsequently, induction of tolerogenic CD11c(+) DCs leads to the generation of hapten-specific CD8(+) Treg cells, which protect against contact hypersensitivity.

Conclusions: Our data demonstrate critical interactions between CD4(+)CD25(+)FOXP3(+) Treg cells and tolerogenic CD8(+)CD11c(+) DCs during the induction of LZT.
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http://dx.doi.org/10.1016/j.jaci.2012.06.022DOI Listing
September 2012

Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells.

Immunity 2012 Aug 16;37(2):264-75. Epub 2012 Aug 16.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.

Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.
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http://dx.doi.org/10.1016/j.immuni.2012.05.025DOI Listing
August 2012

Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction.

Circulation 2011 Sep 29;124(12):1370-81. Epub 2011 Aug 29.

2(nd) Medical Clinic, University Medical Center Mainz, Germany.

Background: Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases. The predominant source of reactive oxygen species, eg, vascular (endothelial, smooth muscle, adventitial) versus phagocytic NADPH oxidase, and the role of myelomonocytic cells in mediating arterial hypertension have not been defined yet.

Methods And Results: Angiotensin II (1 mg · kg(-1) · d(-1) for 7 days) increased the number of both CD11b(+)Gr-1(low)F4/80(+) macrophages and CD11b(+)Gr-1(high)F4/80(-) neutrophils in mouse aorta (verified by flow cytometry). Selective ablation of lysozyme M-positive (LysM(+)) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM(iDTR) mice) reduced the number of monocytes in the circulation and limited ATII-induced infiltration of these cells into the vascular wall, whereas the number of neutrophils was not reduced. Depletion of LysM(+) cells attenuated ATII-induced blood pressure increase (measured by radiotelemetry) and vascular endothelial and smooth muscle dysfunction (assessed by aortic ring relaxation studies) and reduced vascular superoxide formation (measured by chemiluminescence, cytochrome c assay, and oxidative fluorescence microtopography) and the expression of NADPH oxidase subunits gp91(phox) and p67(phox) (assessed by Western blot and mRNA reverse-transcription polymerase chain reaction). Adoptive transfer of wild-type CD11b(+)Gr-1(+) monocytes into depleted LysM(iDTR) mice reestablished ATII-induced vascular dysfunction, oxidative stress, and arterial hypertension, whereas transfer of CD11b(+)Gr-1(+) neutrophils or monocytes from gp91(phox) or ATII receptor type 1 knockout mice did not. CONCLUSIONS- Infiltrating monocytes with a proinflammatory phenotype and macrophages rather than neutrophils appear to be essential for ATII-induced vascular dysfunction and arterial hypertension.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.034470DOI Listing
September 2011

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis.

Brain 2010 Apr 30;133(Pt 4):1067-81. Epub 2010 Mar 30.

Department of Neurology, University Medical Centre Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany.

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing-remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-beta inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-beta on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awq039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850583PMC
April 2010

Nonredundant roles for B cell-derived IL-10 in immune counter-regulation.

J Immunol 2009 Aug 20;183(4):2312-20. Epub 2009 Jul 20.

Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8(+) T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.
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http://dx.doi.org/10.4049/jimmunol.0900185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772089PMC
August 2009

A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes.

Am J Pathol 2009 Jul 15;175(1):132-47. Epub 2009 Jun 15.

Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Whether the wound macrophage is a key regulatory inflammatory cell type in skin repair has been a matter of debate. A transgenic mouse model mediating inducible macrophage depletion during skin repair has not been used to date to address this question. Here, we specifically rendered the monocyte/macrophage leukocyte lineage sensitive to diphtheria toxin by expressing the lysozyme M promoter-driven, Cre-mediated excision of a transcriptional STOP cassette from the simian DT receptor gene in mice (lysM-Cre/DTR). Application of diphtheria toxin to lysM-Cre/DTR mice led to a rapid reduction in both skin tissue and wound macrophage numbers at sites of injury. Macrophage-depleted mice revealed a severely impaired wound morphology and delayed healing. In the absence of macrophages, wounds were re-populated by large numbers of neutrophils. Accordingly, macrophage-reduced wound tissues exhibited the increased and prolonged persistence of macrophage inflammatory protein-2, macrophage chemoattractant protein-1, interleukin-1beta, and cyclooxygenase-2, paralleled by unaltered levels of bioactive transforming growth factor-beta1. Altered expression patterns of vascular endothelial growth factor on macrophage reduction were associated with a disturbed neo-vascularization at the wound site. Impaired wounds revealed a loss of myofibroblast differentiation and wound contraction. Our data in the use of lysM-Cre/DTR mice emphasize the pivotal function of wound macrophages in the integration of inflammation and cellular movements at the wound site to enable efficient skin repair.
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http://dx.doi.org/10.2353/ajpath.2009.081002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708801PMC
July 2009

B7-H1 and CD8+ Treg: the enigmatic role of B7-H1 in peripheral tolerance.

Eur J Immunol 2009 Jun;39(6):1448-51

First Medical Department, University Medicine of the Johannes-Gutenberg University of Mainz, Mainz, Germany.

The interaction between B7-H1 (PD-L1) expressed on APC with PD-1 expressed by T cells was shown previously to result in inhibition of T-cell activation and autoimmune diseases. A paper in this issue of the European Journal of Immunology demonstrates that DC B7-H1 expression can in fact enhance autoimmunity, rather than suppress it. Using a model of direct injection of self antigen-loaded DC into the CNS, the authors demonstrate that DC with intact B7-H1 expression exacerbate CNS autoimmune disease. Importantly, the improved disease outcome in animals treated with B7-H1(-/-) DC is a result of a population of CD8(+) Treg cells that expand at the site of autoimmune inflammation.
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http://dx.doi.org/10.1002/eji.200939541DOI Listing
June 2009