Publications by authors named "Andrew L Croxford"

30 Publications

  • Page 1 of 1

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

Nat Commun 2020 09 21;11(1):4767. Epub 2020 Sep 21.

Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.
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http://dx.doi.org/10.1038/s41467-020-18513-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505844PMC
September 2020

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling.

Cell Rep 2020 03;30(9):3004-3019.e5

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

CSF-1R haploinsufficiency causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Previous studies in the Csf1r mouse model of ALSP hypothesized a central role of elevated cerebral Csf2 expression. Here, we show that monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination. We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in humans. Our data provide insights into the mechanisms underlying ALSP. Because increased CSF2 levels and decreased microglial Csf1r expression have also been reported in Alzheimer's disease and multiple sclerosis, we suggest that the unbalanced CSF-1R/CSF-2 signaling we describe in the present study may contribute to the pathogenesis of other neurodegenerative conditions.
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http://dx.doi.org/10.1016/j.celrep.2020.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370656PMC
March 2020

Plaque-associated myeloid cells derive from resident microglia in an Alzheimer's disease model.

J Exp Med 2020 04;217(4)

Department of Anatomy and Cell Biology, Stark Neuroscience Research Institute, School of Medicine, Indiana University, Indianapolis, IN.

Alzheimer's disease (AD) is accompanied by a robust inflammatory response mediated by plaque-associated myeloid cells of the brain. These cells exhibit altered gene expression profiles and serve as a barrier, preventing neuritic dystrophy. The origin of these cells has been controversial and is of therapeutic importance. Here, we genetically labeled different myeloid populations and unequivocally demonstrated that plaque-associated myeloid cells in the AD brain are derived exclusively from resident microglia, with no contribution from circulating peripheral monocytes.
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http://dx.doi.org/10.1084/jem.20191374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144522PMC
April 2020

Impact of high-altitude therapy on type-2 immune responses in asthma patients.

Allergy 2020 01 3;75(1):84-94. Epub 2019 Nov 3.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.

Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma.

Methods: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry.

Results: The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4 and CD8 T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2 Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4 and CD8 T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2 Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2 Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels.

Conclusions: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions.
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http://dx.doi.org/10.1111/all.13967DOI Listing
January 2020

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

BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis.

J Exp Med 2016 07 18;213(8):1537-53. Epub 2016 Jul 18.

Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, S-171 76 Stockholm, Sweden

Prolonged infections or adjuvant usage can trigger emergency granulopoiesis (EG), leading to dysregulation in neutrophil blood counts. However, the impact of EG on T and B cell function remains largely unknown. In this study, to address this question, we used a mouse model of neutropenia and studied immune activation after adjuvant administration. The initial neutropenic state fostered an environment of increased dendritic cell activation and T cell-derived IL-17 production. Interestingly, neutropenic lysozyme 2-diphtheria toxin A mice exhibited striking EG and amplified neutrophil recruitment to the lymph nodes (LNs) that was dependent on IL-17-induced prostaglandin activity. The recruited neutrophils secreted a B cell-activating factor that highly accelerated plasma cell generation and antigen-specific antibody production. Reduction of neutrophil functions via granulocyte colony-stimulating factor neutralization significantly diminished plasma cell formation, directly linking EG with the humoral immune response. We conclude that neutrophils are capable of directly regulating T cell-dependent B cell responses in the LN.
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http://dx.doi.org/10.1084/jem.20150577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986521PMC
July 2016

Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.

Sci Transl Med 2016 Mar 16;8(330):330ra37. Epub 2016 Mar 16.

Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.

Inflammation has important roles in tissue regeneration, autoimmunity, and cancer. Different inflammatory stimuli can lead to bone loss by mechanisms that are not well understood. We show that skin inflammation induces bone loss in mice and humans. In psoriasis, one of the prototypic IL-17A-mediated inflammatory human skin diseases, low bone formation and bone loss correlated with increased serum IL-17A levels. Similarly, in two mouse models with chronic IL-17A-mediated skin inflammation,K14-IL17A(ind)andJunB(Δep), strong inhibition of bone formation was observed, different from classical inflammatory bone loss where osteoclast activation leads to bone degradation. We show that under inflammatory conditions, skin-resident cells such as keratinocytes, γδ T cells, and innate lymphoid cells were able to express IL-17A, which acted systemically to inhibit osteoblast and osteocyte function by a mechanism involving Wnt signaling. IL-17A led to decreased Wnt signaling in vitro, and importantly, pharmacological blockade of IL-17A rescued Wnt target gene expression and bone formation in vivo. These data provide a mechanism where IL-17A affects bone formation by regulating Wnt signaling in osteoblasts and osteocytes. This study suggests that using IL-17A blocking agents in psoriasis could be beneficial against bone loss in these patients.
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http://dx.doi.org/10.1126/scitranslmed.aad8996DOI Listing
March 2016

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

Nat Commun 2016 Mar 11;7:10973. Epub 2016 Mar 11.

Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.

Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.
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http://dx.doi.org/10.1038/ncomms10973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793047PMC
March 2016

IL17A-Mediated Endothelial Breach Promotes Metastasis Formation.

Cancer Immunol Res 2016 Jan 19;4(1):26-32. Epub 2015 Nov 19.

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

The role of the IL23/IL17A axis in tumor-immune interactions is a matter of controversy. Although some suggest that IL17A-producing T cells (TH17) can suppress tumor growth, others report that IL17A and IL23 accelerate tumor growth. Here, we systematically assessed the impact of IL17A-secreting lymphocytes in several murine models of tumor lung metastasis. Genetic fate mapping revealed that IL17A was secreted within lung metastases predominantly by γδ T cells, whereas TH17 cells were virtually absent. Using different tumor models, we found Il17a(-/-) mice to consistently develop fewer pulmonary tumor colonies. IL17A specifically increased blood vessel permeability and the expression of E-selectin and VCAM-1 by lung endothelial cells in vivo. In transgenic mice, specific targeting of IL17A to the endothelium increased the number of tumor foci. Moreover, the direct impact of IL17A on lung endothelial cells resulted in impaired endothelial barrier integrity, showing that IL17A promotes the formation of lung metastases through tumor-endothelial transmigration.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0154DOI Listing
January 2016

GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage.

Trends Immunol 2015 Oct;36(10):651-662

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address:

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS). MS lesions harbor different immune cells, but the contribution of individual cell types to disease etiology and progression is not well understood. In experimental autoimmune encephalomyelitis (EAE), auto-reactive helper T (Th) cells instigate CNS inflammation by acting on myeloid cells via the production of granulocyte-macrophage colony-stimulating factor (GM-CSF). Recent reports have implicated myeloid cells in both the inflammatory process and as executers of tissue damage in the CNS. We review these findings here, and integrate them into a model wherein GM-CSF produced by Th cells coordinates monocyte recruitment to the CNS, and differentiation into pathogenic effectors. We discuss the implications of this model to current therapies for MS, and outline important areas of further inquiry.
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http://dx.doi.org/10.1016/j.it.2015.08.004DOI Listing
October 2015

The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity.

Immunity 2015 Sep 1;43(3):502-14. Epub 2015 Sep 1.

Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland. Electronic address:

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations throughout the myeloid lineages. Experimental autoimmune encephalomyelitis (EAE) progressed normally when either classical dendritic cells (cDCs) or neutrophils lacked GM-CSF responsiveness. The development of tissue-invading monocyte-derived dendritic cells (moDCs) was also unperturbed upon Csf2rb deletion. Instead, deletion of Csf2rb in CCR2(+)Ly6C(hi) monocytes phenocopied the EAE resistance seen in complete Csf2rb-deficient mice. High-dimensional analysis of tissue-infiltrating moDCs revealed that GM-CSF initiates a combination of inflammatory mechanisms. These results indicate that GM-CSF signaling controls a pathogenic expression signature in CCR2(+)Ly6C(hi) monocytes and their progeny, which was essential for tissue damage.
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http://dx.doi.org/10.1016/j.immuni.2015.08.010DOI Listing
September 2015

Dermal IL-17-producing γδ T cells establish long-lived memory in the skin.

Eur J Immunol 2015 Nov 19;45(11):3022-33. Epub 2015 Oct 19.

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

Conventional αβ T cells have the ability to form a long-lasting resident memory T-cell (TRM ) population in nonlymphoid tissues after encountering foreign antigen. Conversely, the concept of 'innate memory', where the ability of nonadaptive branches of the immune system to deliver a rapid, strengthened immune response upon reinfection or rechallenge, is just emerging. Using the αβ T-cell-independent Aldara psoriasis mouse model in combination with genetic fate-mapping and reporter systems, we identified a subset of γδ T cells in mice that is capable of establishing a long-lived memory population in the skin. IL-17A/F-producing Vγ4(+) Vδ4(+) T cells populate and persist in the dermis for long periods of time after initial stimulation with Aldara. Experienced Vγ4(+) Vδ4(+) cells show enhanced effector functions and mediate an exacerbated secondary inflammatory response. In addition to identifying a unique feature of γδ T cells during inflammation, our results have direct relevance to the human disease as this quasi-innate memory provides a mechanistic insight into relapses and chronification of psoriasis.
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http://dx.doi.org/10.1002/eji.201545883DOI Listing
November 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

IL-12-and IL-23 in health and disease.

Cytokine Growth Factor Rev 2014 Aug 1;25(4):415-21. Epub 2014 Aug 1.

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

Interleukin (IL)-12 and IL-23 play important roles in the development of experimental autoimmune disease models and numerous afflictions affecting humans. Preclinical data over the last 20 years combined with successful clinical trials has identified a clear relationship between IL-12, IL-23 and the generation of pathogenic T helper cells capable of orchestrating tissue inflammation. Observations made in the clinic have shown that IL-12p40, a common subunit shared by IL-12 and IL-23, is critical to pathologies associated with psoriasis, inflammatory bowel disease (IBD) and tumor growth. These advancements have set in motion the development of a number of potential therapeutics aimed at manipulating IL-12/23 signaling pathways in both mice and humans. This review will discuss a brief history of the understanding and expansion of the IL-12 cytokine family, some difficulties associated with preclinical data interpretation and finally the medicinal interventions that have been developed to combat IL-12/23-driven autoimmune disorders.
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http://dx.doi.org/10.1016/j.cytogfr.2014.07.017DOI Listing
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

Does dietary salt induce autoimmunity?

Cell Res 2013 Jul 7;23(7):872-3. Epub 2013 May 7.

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

Two recent publications suggest that dietary salt may polarize TH17 cells and therefore increase the risk of developing autoimmune disease. Where low salt diets can readily be tested for their therapeutic effects in autoimmune disease, more work is needed to connect dietary salts with the development of immunopathology.
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http://dx.doi.org/10.1038/cr.2013.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698635PMC
July 2013

A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells.

Nature 2013 Feb 16;494(7436):261-5. Epub 2013 Jan 16.

Institute of Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.

At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORγt(+) ILCs have been described but the transcriptional programs controlling their specification and fate remain largely unknown. Here we provide evidence that the transcription factor T-bet determines the fate of a distinct lineage of CCR6(-)RORγt(+) ILCs. Postnatally emerging CCR6(-)RORγt(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)RORγt(+) ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6(-)RORγt(+) ILCs, but they could not differentiate into NKp46-expressing RORγt(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells) and failed to produce IFN-γ. The production of IFN-γ by T-bet-expressing CCR6(-)RORγt(+) ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)RORγt(+) ILCs facilitates the differentiation of IFN-γ-producing CCR6(-)RORγt(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORγt, which is also found in subsets of IL-17-producing T-helper (T(H)17) cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology.
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http://dx.doi.org/10.1038/nature11813DOI Listing
February 2013

IL-23: one cytokine in control of autoimmunity.

Eur J Immunol 2012 Sep;42(9):2263-73

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

During the past decade, it has been firmly established that IL-23 is essential for disease development in several models of autoimmune disease, including psoriatic skin inflammation, inflammatory bowel disease (IBD), and experimental autoimmune encephalomyelitis (EAE). The mechanism by which IL-23 exerts its pathogenic role has been mostly scrutinized in the context of Th17 cells, which were thought to mediate autoimmunity by secretion of IL-17 family cytokines. However, the picture emerging now is one of multiple IL-23-responsive cell types, pro-inflammatory cytokine induction, and pathogenic "licensing" following an IL-23-dominated interaction between the T cell and the antigen-presenting cell (APC). This review will focus on our changing view of IL-23-dependent autoimmune pathologies with a particular emphasis on the responder cells and their IL-23-induced factors that ultimately mediate tissue destruction.
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http://dx.doi.org/10.1002/eji.201242598DOI Listing
September 2012

Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS.

Nat Neurosci 2011 Dec 4;15(1):98-106. Epub 2011 Dec 4.

Department of Neuropathology, University of Freiburg, Freiburg, Germany.

The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.
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http://dx.doi.org/10.1038/nn.2964DOI Listing
December 2011

Genetic proof for the transient nature of the Th17 phenotype.

Eur J Immunol 2010 Dec;40(12):3336-46

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

IL-17-producing CD4(+) T cells (Th17) have been classified as a new T helper cell subset. Using an IL-17 fate mapping mouse strain, which genetically fixes the memory of IL-17 expression, we demonstrate that IL-17A/F-expressing T helper cells generated either in vitro or in vivo are not a stable T-cell subset. Upon adoptive transfer of IL-17F-reporter-positive Th17 cells to RAG-deficient or WT animals, encephalitogenic Th17 cells partially lose IL-17 expression and upregulate IFN-γ. Additionally, we show that Th1 cells can convert in vivo to IL-17A/IFN-γ-coexpressing cells in the mesenteric lymph nodes (mLN). Our data classify IL-17A and IL-17F as cytokines produced transiently in response to the local microenvironment, thus showing that IL-17 expression does not define an end-stage T helper cell subset.
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http://dx.doi.org/10.1002/eji.201040755DOI Listing
December 2010

Cytokine reporter mice in immunological research: perspectives and lessons learned.

Immunology 2011 Jan 11;132(1):1-8. Epub 2010 Nov 11.

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

Cytokines are soluble messenger molecules with important regulatory functions throughout the immune system. 'Cytokine reporter' strains express marker molecules under control of elements from cytokine genes allowing for easy identification of their cellular sources. Such systems are well-accepted tools for research of cytokine function. The value of these strains lies in the ability to perform experiments relying on identification and isolation of live cytokine-expressing cells, provided that the reporter faithfully reflects the proper cytokine mRNA and protein production. As more diverse cell subsets are defined by their cytokine expression, the field has adapted with the generation of more sophisticated strains. In this review we summarize the evolution of cytokine detection methods and give examples of knowledge gained using cytokine reporter mice for cell types expressing interferon-γ and interleukin-4, -10 and -17. We also discuss current options for generating such reporter strains and their potential pitfalls.
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http://dx.doi.org/10.1111/j.1365-2567.2010.03372.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015069PMC
January 2011

Mouse models for multiple sclerosis: historical facts and future implications.

Biochim Biophys Acta 2011 Feb 25;1812(2):177-83. Epub 2010 Jun 25.

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

Multiple sclerosis (MS) is an inflammatory and demyelinating condition of the CNS, characterized by perivascular infiltrates composed largely of T lymphocytes and macrophages. Although the precise cause remains unknown, numerous avenues of research support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Pathologically similar lesions to those seen in MS can be induced in laboratory rodents by immunization with CNS-derived antigens. This form of disease induction, broadly termed experimental autoimmune encephalomyelitis, is frequently the starting point in MS research with respect to studying pathogenesis and creating novel treatments. Many different EAE models are available, each mimicking a particular facet of MS. These models all have common ancestry, and have developed from a single concept of immunization with self-antigen. We will discuss the major changes in immunology research, which have shaped the EAE models we use today, and discuss how current animal models of MS have resulted in successful treatments and more open questions for researchers to address.
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http://dx.doi.org/10.1016/j.bbadis.2010.06.010DOI Listing
February 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

Cutting edge: an IL-17F-CreEYFP reporter mouse allows fate mapping of Th17 cells.

J Immunol 2009 Feb;182(3):1237-41

First Medical Department, Johannes Gutenberg University of Mainz, Mainz, Germany.

The need for reporter lines able to faithfully track Th17 cells in vivo has become an issue of exceptional importance. To address this, we generated a mouse strain in which Cre recombinase is expressed from the IL-17F promoter. Crossing the IL-17F-Cre allele to a conditional enhanced yellow fluorescent protein (EYFP) reporter mouse yielded the IL-17F-Cre(EYFP) strain, in which IL-17F expression is twinned with EYFP in live IL-17F-expressing cells. Although we demonstrate that IL-17F expression is restricted to CD4(+) T cells during experimental autoimmune encephalomyelitis, IL-17F-Cre(EYFP) CD8 T cells robustly expressed IL-17F in response to TGF-beta, IL-6, and IL-23. Fate mapping of IL-17F-expressing reporter T cells revealed a significant down-regulation of Th17 cytokines after homeostatic expansion in RAG1-deficient animals. Despite this loss of effector phenotype, committed Th17 cells were resistant to Foxp3 expression in vitro or in vivo. Thus, the IL-17F-Cre strain furthers our understanding of Th17 biology.
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http://dx.doi.org/10.4049/jimmunol.182.3.1237DOI Listing
February 2009

IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice.

J Clin Invest 2009 Jan 15;119(1):61-9. Epub 2008 Dec 15.

Neuroimmunology Division, Institute of Experimental Immunology, Department of Pathology, University Hospital Zurich, Zurich, Switzerland.

The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell-specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell-driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F-deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F-deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease.
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http://dx.doi.org/10.1172/JCI35997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613466PMC
January 2009

IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells.

Proc Natl Acad Sci U S A 2008 Nov 17;105(47):18460-5. Epub 2008 Nov 17.

Technische Universität München, Department of Neurology, Ismaninger Strasse 22, 81675 München, Germany.

The conditions leading to the induction of adaptive Foxp3(+) regulatory T cells (T-regs) from peripheral T cells in vivo are incompletely understood. Here, we show that unresponsiveness of T cells to IL-6 by T cell-selective deletion of gp130 or immunization of wild-type mice with antigen in incomplete Freund's adjuvant (IFA), which fails to induce IL-6, promotes the conversion of peripheral CD4(+) T cells into adaptive Foxp3(+) T-regs. Thus, both T cell-conditional gp130 knockout (KO) mice immunized with MOG35-55 in complete Freund's adjuvant (CFA) and wild-type mice immunized with MOG35-55 in IFA develop overwhelming antigen-specific T-reg responses and are protected from experimental autoimmune encephalomyelitis (EAE). Depletion of T-regs restores T helper (Th)17 responses and clinical EAE in MOG/CFA-immunized T cell-conditional gp130 KO mice, but not in MOG/IFA-immunized wild-type mice. We conclude that in the absence of T-regs, IL-6 signaling is dispensable for the induction of Th17 cells, and alternative pathways exist to induce Th17 cells and EAE in the absence of IL-6 signaling. However, IL-6 signaling is dominant in inhibiting the conversion of conventional T cells into Foxp3(+) T-regs in vivo, and in the absence of IL-6 signaling, no other cytokine can substitute in inhibiting T-reg conversion. These data identify IL-6 as an important target to modulate autoimmune responses and chronic inflammation.
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http://dx.doi.org/10.1073/pnas.0809850105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587589PMC
November 2008

New tools to study the role of B cells in cytomegalovirus infections.

Med Microbiol Immunol 2008 Jun 11;197(2):145-9. Epub 2008 Mar 11.

1st Medical Department, University of Mainz, Obere-Zahlbacherstr. 63, 55131 Mainz, Germany.

B cells were previously shown to mediate partial protection against CMV infection, as in the absence of B cells, latently infected mice were more susceptible to virus reactivation. It remains unclear if this effect stems from the loss of B cells as antibody producers or as antigen presenting cells. To address this fundamental question, we propose to make use of new mouse models that allow conditional ablation of B cells or that allow for the generation of mice with B cells that are not able to produce antibodies.
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http://dx.doi.org/10.1007/s00430-008-0088-zDOI Listing
June 2008

MHC-restricted T cell receptor signaling is required for alpha beta TCR replacement of the pre T cell receptor.

Eur J Immunol 2008 Feb;38(2):391-9

Institute for Genetics, University of Cologne, Cologne, Germany.

A developmental block is imposed on CD25(+)CD44(-) thymocytes at the beta-selection checkpoint in the absence of the pre T cell receptor (preTCR) alpha-chain, pTalpha. Early surface expression of a transgenic alphabeta TCR has been shown to partially circumvent this block, such that thymocytes progress to the CD4(+)CD8(+) double-positive stage. We wanted to analyze whether a restricting MHC element is required for alphabeta TCR-expressing double-negative (DN) thymocytes to overcome the developmental block in pTalpha-deficient animals. We used the HY-I knock-in model that endows thymocytes with alphabeta TCR expression in the DN compartment but has the advantage of physiological expression levels, in contrast to conventional TCR transgenes. On a pTalpha-deficient background, this HY-I TCR transgene 'rescued' CD25(+)CD44(-) thymocytes from apoptosis and enabled progression to later differentiation stages. On a non-selecting MHC background, however, pTalpha-deficient HY-I mice presented a pronounced reduction in numbers of splenocytes and thymocytes when compared to animals of selecting MHC genotype, showing that MHC restriction is necessary to drive HY-TCR-mediated rescue of pTalpha-deficient thymocytes.
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http://dx.doi.org/10.1002/eji.200737054DOI Listing
February 2008