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Krupa P, Wein H, Zemmrich LS, Zygmunt M, Muzzio DO. Pregnancy-related factors induce immune tolerance through regulation of sCD83 release. Front Immunol 2024; 15:1452879. [PMID: 39328416 PMCID: PMC11424458 DOI: 10.3389/fimmu.2024.1452879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
A well-balanced maternal immune system is crucial to maintain fetal tolerance in case of infections during pregnancy. Immune adaptations include an increased secretion of soluble mediators to protect the semi-allogeneic fetus from excessive pro-inflammatory response. B lymphocytes acquire a higher capacity to express CD83 and secrete soluble CD83 (sCD83) upon exposure to bacteria-derived components such as LPS. CD83 possesses immune modulatory functions and shows a promising therapeutic potential against inflammatory conditions. The administration of sCD83 to pregnant mice reduces LPS-induced abortion rates. The increased CD83 expression by endometrial B cells as compared to peripheral blood B cells suggests its modulatory role in the fetal tolerance, especially in the context of infection. We postulate that in pregnancy, CD83 expression and release is controlled by pregnancy-related hormones. The intra- and extracellular expression of CD83 in leukocytes from peripheral blood or decidua basalis and parietalis at term were analyzed by flow cytometry. After treatment with pregnancy-related hormones and LPS, ELISA and qPCR were performed to study sCD83 release and CD83 gene expression, respectively. Cleavage prediction analysis was used to find potential proteases targeting CD83. Expression of selected proteases was analyzed by ELISA. Higher levels of CD83 were found in CD11c+ dendritic cells, CD3+ T cells and CD19+ B cells from decidua basalis and decidua parietalis after LPS-stimulation in vitro. An increase of intracellular expression of CD83 was also detected in CD19+ B cells from both compartments. Stimulated B cells displayed significantly higher percentages of CD83+ cells than dendritic cells and T cells from decidua basalis and peripheral blood. Treatment of B lymphocytes with pregnancy-related molecules (E2, P4, TGF-β1 and hCG) enhanced the LPS-mediated increase of CD83 expression, while dexamethasone led to a reduction. Similarly, the release of sCD83 was increased under TGF-β1 treatment but decreased upon dexamethasone stimulation. Finally, we found that the hormonal regulation of CD83 expression is likely a result from a balance between gene transcription from CD83 and the modulation of the metalloproteinase MMP-7. Thus, data supports and complements our previous murine studies on hormonal regulation of CD83 expression, reinforcing its immunomodulatory relevance in anti-bacterial responses during pregnancy.
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Affiliation(s)
| | | | | | | | - Damián Oscar Muzzio
- Research Laboratory, Department of Obstetrics and Gynecology, University Medicine
Greifswald, Greifswald, Germany
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2
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Ryu HM, Islam SMS, Riaz B, Sayeed HM, Choi B, Sohn S. Immunomodulatory Effects of a Probiotic Mixture: Alleviating Colitis in a Mouse Model through Modulation of Cell Activation Markers and the Gut Microbiota. Int J Mol Sci 2024; 25:8571. [PMID: 39201260 PMCID: PMC11354276 DOI: 10.3390/ijms25168571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Ulcerative colitis (UC) is a persistent inflammatory intestinal disease that consistently affects the colon and rectum. Its exact cause remains unknown. UC causes a considerable challenge in healthcare, prompting research for novel therapeutic strategies. Although probiotics have gained popularity as possible candidates for managing UC, studies are still ongoing to identify the best probiotics or probiotic mixtures for clinical applications. This study aimed to determine the efficacy of a multi-strain probiotic mixture in mitigating intestinal inflammation in a colitis mouse model induced by dextran sulfate sodium. Specifically, a multi-strain probiotic mixture consisting of Tetragenococcus halophilus and Eubacterium rectale was used to study its impact on colitis symptoms. Anti-inflammatory effects were evaluated using ELISA and flow cytometry. The configuration of gut microbial communities was determined using 16S rRNA metagenomic analysis. According to this study, colitis mice treated with the probiotic mixture experienced reduced weight loss and significantly less colonic shortening compared to untreated mice. Additionally, the treated mice exhibited increased levels of forkhead box P3 (Foxp3) and interleukin 10, along with decreased expression of dendritic cell activation markers, such as CD40+, CD80+, and CD83+, in peripheral blood leukocytes and intraepithelial lymphocytes. Furthermore, there was a significant decrease in the frequencies of CD8+N.K1.1+ cells and CD11b+Ly6G+ cells. In terms of the gut microbiota, probiotic-mixture treatment of colitis mice significantly increased the abundance of the phyla Actinobacteria and Verrucomicrobia (p < 0.05). These results provide valuable insights into the therapeutic promise of multi-strain probiotics, shedding light on their potential to alleviate colitis symptoms. This research contributes to the ongoing exploration of effective probiotic interventions for managing inflammatory bowel disease.
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Affiliation(s)
- Hye-Myung Ryu
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - S. M. Shamsul Islam
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (S.M.S.I.); (B.R.); (H.M.S.)
| | - Bushra Riaz
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (S.M.S.I.); (B.R.); (H.M.S.)
| | - Hasan M. Sayeed
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (S.M.S.I.); (B.R.); (H.M.S.)
| | - Bunsoon Choi
- Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Seonghyang Sohn
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea; (S.M.S.I.); (B.R.); (H.M.S.)
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3
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Ghiboub M, Bell M, Sinkeviciute D, Prinjha RK, de Winther MPJ, Harker NR, Tough DF, de Jonge WJ. The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential. Curr Issues Mol Biol 2023; 45:4228-4245. [PMID: 37232738 DOI: 10.3390/cimb45050269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/04/2023] [Accepted: 05/08/2023] [Indexed: 05/27/2023] Open
Abstract
SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.
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Affiliation(s)
- Mohammed Ghiboub
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Matthew Bell
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Dovile Sinkeviciute
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Rab K Prinjha
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Menno P J de Winther
- Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Department of Medicine, Institute for Cardiovascular Prevention (IPEK), 80336 Munich, Germany
| | - Nicola R Harker
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - David F Tough
- Immunology Research Unit, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
- Department of Surgery, University of Bonn, 53127 Bonn, Germany
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4
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Riaz B, Islam SMS, Ryu HM, Sohn S. CD83 Regulates the Immune Responses in Inflammatory Disorders. Int J Mol Sci 2023; 24:ijms24032831. [PMID: 36769151 PMCID: PMC9917562 DOI: 10.3390/ijms24032831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Activating the immune system plays an important role in maintaining physiological homeostasis and defending the body against harmful infections. However, abnormalities in the immune response can lead to various immunopathological responses and severe inflammation. The activation of dendritic cells (DCs) can influence immunological responses by promoting the differentiation of T cells into various functional subtypes crucial for the eradication of pathogens. CD83 is a molecule known to be expressed on mature DCs, activated B cells, and T cells. Two isotypes of CD83, a membrane-bound form and a soluble form, are subjects of extensive scientific research. It has been suggested that CD83 is not only a ubiquitous co-stimulatory molecule but also a crucial player in monitoring and resolving inflammatory reactions. Although CD83 has been involved in immunological responses, its functions in autoimmune diseases and effects on pathogen immune evasion remain unclear. Herein, we outline current immunological findings and the proposed function of CD83 in inflammatory disorders.
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Affiliation(s)
- Bushra Riaz
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - S. M. Shamsul Islam
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Hye Myung Ryu
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Seonghyang Sohn
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Correspondence:
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5
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Liu C, Zhu J, Mi Y, Jin T. Impact of disease-modifying therapy on dendritic cells and exploring their immunotherapeutic potential in multiple sclerosis. J Neuroinflammation 2022; 19:298. [PMID: 36510261 PMCID: PMC9743681 DOI: 10.1186/s12974-022-02663-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response based on their subtypes and environmental signals. Emerging evidence indicates that DCs are critical for initiation and progression of autoimmune diseases, including multiple sclerosis (MS). Current disease-modifying therapies (DMT) for MS can significantly affect DCs' functions. However, the study on the impact of DMT on DCs is rare, unlike T and B lymphocytes that are the most commonly discussed targets of these therapies. Induction of tolerogenic DCs (tolDCs) with powerful therapeutic potential has been well-established to combat autoimmune responses in laboratory models and early clinical trials. In contrast to in vitro tolDC induction, in vivo elicitation by specifically targeting multiple cell-surface receptors has shown greater promise with more advantages. Here, we summarize the role of DCs in governing immune tolerance and in the process of initiating and perpetuating MS as well as the effects of current DMT drugs on DCs. We then highlight the most promising cell-surface receptors expressed on DCs currently being explored as the viable pharmacological targets through antigen delivery to generate tolDCs in vivo.
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Affiliation(s)
- Caiyun Liu
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jie Zhu
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China ,grid.24381.3c0000 0000 9241 5705Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrcs, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Yan Mi
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Tao Jin
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
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6
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Hu Y, Hudson WH, Kissick HT, Medina CB, Baptista AP, Ma C, Liao W, Germain RN, Turley SJ, Zhang N, Ahmed R. TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection. J Exp Med 2022; 219:e20211574. [PMID: 35980386 PMCID: PMC9393409 DOI: 10.1084/jem.20211574] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 06/01/2022] [Accepted: 07/20/2022] [Indexed: 12/24/2022] Open
Abstract
Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.
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Affiliation(s)
- Yinghong Hu
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
| | - William H. Hudson
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
| | - Haydn T. Kissick
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
- Winship Cancer Institute of Emory University, Atlanta, GA
- Department of Urology, Emory University School of Medicine, Atlanta, GA
| | - Christopher B. Medina
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
| | - Antonio P. Baptista
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Chaoyu Ma
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Wei Liao
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ronald N. Germain
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | | | - Nu Zhang
- Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Rafi Ahmed
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
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Royzman D, Peckert-Maier K, Stich L, König C, Wild AB, Tauchi M, Ostalecki C, Kiesewetter F, Seyferth S, Lee G, Eming SA, Fuchs M, Kunz M, Stürmer EK, Peters EMJ, Berking C, Zinser E, Steinkasserer A. Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages. Front Immunol 2022; 13:1012647. [PMID: 36248909 PMCID: PMC9564224 DOI: 10.3389/fimmu.2022.1012647] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022] Open
Abstract
To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1β, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.
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Affiliation(s)
- Dmytro Royzman
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
| | - Katrin Peckert-Maier
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christina König
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Miyuki Tauchi
- Department of Internal Medicine 2, University Hospital Erlangen, FAU, Erlangen, Germany
| | - Christian Ostalecki
- Department of Dermatology, University Hospital Erlangen, FAU, Erlangen, Germany
| | | | - Stefan Seyferth
- Division of Pharmaceutics, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Geoffrey Lee
- Division of Pharmaceutics, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Sabine A. Eming
- Department of Dermatology, University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster Cluster of Excellence for Aging Research (CECAD), University of Cologne, Cologne, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Meik Kunz
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
- Department of Medical Informatics, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany
| | - Ewa K. Stürmer
- Department for Vascular Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eva M. J. Peters
- Psychoneuroimmunology Laboratory, Klinik für Psychosomatik und Psychotherapie, Justus-Liebig Universität Gießen, Gießen, Germany
| | - Carola Berking
- Department of Dermatology, University Hospital Erlangen, FAU, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
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8
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Royzman D, Andreev D, Stich L, Peckert-Maier K, Wild AB, Zinser E, Mühl-Zürbes P, Jones E, Adam S, Frey S, Fuchs M, Kunz M, Bäuerle T, Nagel L, Schett G, Bozec A, Steinkasserer A. The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis. Front Immunol 2022; 13:936995. [PMID: 36003376 PMCID: PMC9393726 DOI: 10.3389/fimmu.2022.936995] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/08/2022] [Indexed: 12/29/2022] Open
Abstract
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1β, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP+ osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
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Affiliation(s)
- Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
| | - Darja Andreev
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Evan Jones
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Susanne Adam
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Silke Frey
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Meik Kunz
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
- Department of Medical Informatics, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
| | - Tobias Bäuerle
- Institute of Radiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Nagel
- Institute of Radiology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
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9
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Tetragenococcus halophilus Alleviates Intestinal Inflammation in Mice by Altering Gut Microbiota and Regulating Dendritic Cell Activation via CD83. Cells 2022; 11:cells11121903. [PMID: 35741032 PMCID: PMC9221263 DOI: 10.3390/cells11121903] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 01/27/2023] Open
Abstract
Ulcerative colitis (UC) is one of the major subtypes of inflammatory bowel disease with unknown etiology. Probiotics have recently been introduced as a treatment for UC. Tetragenococcus halophilus (T. halophilus) is a lactic acid-producing bacterium that survives in environments with high salt concentrations, though little is known about its immunomodulatory function as a probiotic. The purpose of this study is to determine whether T. halophilus exerts an anti-inflammatory effect on intestinal inflammation in mice. Colitis was induced in C57BL/6J mice by feeding 4% DSS in drinking water for 7 days. T. halophilus was orally administered with DSS. Anti-inflammatory functions were subsequently evaluated by flow cytometry, qRT-PCT, and ELISA. Gut microbial composition was analyzed by 16S rRNA metagenomic analysis. DSS-induced colitis mice treated with T. halophilus showed less weight loss and significantly suppressed colonic shortening compared to DSS-induced colitis mice. T. halophilus significantly reduced the frequency of the dendritic cell activation molecule CD83 in peripheral blood leukocytes and intestinal epithelial lymphocytes. Frequencies of CD8+NK1.1+ cells decreased in mice with colitis after T. halophilus treatment and IL-1β levels were also reduced. Alteration of gut microbiota was observed in mice with colitis after administration of T. halophilus. These results suggest T. halophilus is effective in alleviating DSS-induced colitis in mice by altering immune regulation and gut microbiome compositions.
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10
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Silveira PA, Kupresanin F, Romano A, Hsu WH, Lo TH, Ju X, Chen HT, Roberts H, Baker DG, Clark GJ. Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis. Front Immunol 2022; 13:784528. [PMID: 35222372 PMCID: PMC8866188 DOI: 10.3389/fimmu.2022.784528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Antibodies targeting the activation marker CD83 can achieve immune suppression by targeting antigen-presenting mature dendritic cells (DC). This study investigated the immunosuppressive mechanisms of anti-CD83 antibody treatment in mice and tested its efficacy in a model of autoimmune rheumatoid arthritis. A rat anti-mouse CD83 IgG2a monoclonal antibody, DCR-5, was developed and functionally tested in mixed leukocyte reactions, demonstrating depletion of CD83+ conventional (c)DC, induction of regulatory DC (DCreg), and suppression of allogeneic T cell proliferation. DCR-5 injection into mice caused partial splenic cDC depletion for 2-4 days (mostly CD8+ and CD83+ cDC affected) with a concomitant increase in DCreg and regulatory T cells (Treg). Mice with collagen induced arthritis (CIA) treated with 2 or 6 mg/kg DCR-5 at baseline and every three days thereafter until euthanasia at day 36 exhibited significantly reduced arthritic paw scores and joint pathology compared to isotype control or untreated mice. While both doses reduced anti-collagen antibodies, only 6 mg/kg achieved significance. Treatment with 10 mg/kg DCR-5 was ineffective. Immunohistological staining of spleens at the end of CIA model with CD11c, CD83, and FoxP3 showed greater DC depletion and Treg induction in 6 mg/kg compared to 10 mg/kg DCR-5 treated mice. In conclusion, DCR-5 conferred protection from arthritis by targeting CD83, resulting in selective depletion of mature cDC and subsequent increases in DCreg and Treg. This highlights the potential for anti-CD83 antibodies as a targeted therapy for autoimmune diseases.
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Affiliation(s)
- Pablo A Silveira
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Fiona Kupresanin
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
| | - Adelina Romano
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
| | - Wei-Hsun Hsu
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Tsun-Ho Lo
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
| | - Xinsheng Ju
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Hsiao-Ting Chen
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | | | | | - Georgina J Clark
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,Kira Biotech Pty Ltd., Brisbane, QLD, Australia
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11
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Peckert-Maier K, Schönberg A, Wild AB, Royzman D, Braun G, Stich L, Hadrian K, Tripal P, Cursiefen C, Steinkasserer A, Zinser E, Bock F. Pre-incubation of corneal donor tissue with sCD83 improves graft survival via the induction of alternatively activated macrophages and tolerogenic dendritic cells. Am J Transplant 2022; 22:438-454. [PMID: 34467638 DOI: 10.1111/ajt.16824] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 08/02/2021] [Accepted: 08/22/2021] [Indexed: 01/25/2023]
Abstract
Immune responses reflect a complex interplay of cellular and extracellular components which define the microenvironment of a tissue. Therefore, factors that locally influence the microenvironment and re-establish tolerance might be beneficial to mitigate immune-mediated reactions, including the rejection of a transplant. In this study, we demonstrate that pre-incubation of donor tissue with the immune modulator soluble CD83 (sCD83) significantly improves graft survival using a high-risk corneal transplantation model. The induction of tolerogenic mechanisms in graft recipients was achieved by a significant upregulation of Tgfb, Foxp3, Il27, and Il10 in the transplant and an increase of regulatory dendritic cells (DCs), macrophages (Mφ), and T cells (Tregs) in eye-draining lymph nodes. The presence of sCD83 during in vitro DC and Mφ generation directed these cells toward a tolerogenic phenotype leading to reduced proliferation-stimulating activity in MLRs. Mechanistically, sCD83 induced a tolerogenic Mφ and DC phenotype, which favors Treg induction and significantly increased transplant survival after adoptive cell transfer. Conclusively, pre-incubation of corneal grafts with sCD83 significantly prolongs graft survival by modulating recipient Mφ and DCs toward tolerance and thereby establishing a tolerogenic microenvironment. This functional strategy of donor graft pre-treatment paves the way for new therapeutic options in the field of transplantation.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Alfrun Schönberg
- Department of Experimental Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Andreas B Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Gabriele Braun
- Department of Experimental Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Karina Hadrian
- Department of Experimental Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philipp Tripal
- Optical Imaging Centre, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Claus Cursiefen
- Department of Experimental Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | | | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Felix Bock
- Department of Experimental Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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12
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Peckert-Maier K, Royzman D, Langguth P, Marosan A, Strack A, Sadeghi Shermeh A, Steinkasserer A, Zinser E, Wild AB. Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation. Int J Mol Sci 2022; 23:732. [PMID: 35054916 PMCID: PMC8775349 DOI: 10.3390/ijms23020732] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a "pro-resolution" therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.
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Affiliation(s)
- Katrin Peckert-Maier
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander Universität—Erlangen-Nürnberg, 91052 Erlangen, Germany; (D.R.); (P.L.); (A.M.); (A.S.); (A.S.S.); (A.S.); (E.Z.)
| | | | | | | | | | | | | | | | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander Universität—Erlangen-Nürnberg, 91052 Erlangen, Germany; (D.R.); (P.L.); (A.M.); (A.S.); (A.S.S.); (A.S.); (E.Z.)
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13
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Zhao J, Wang Y, Wang W, Tian Y, Gan Z, Wang Y, He H, Chen W, Zhang X, Wu Y, Jia R, Shi M, Wei W, Ma G. In situ growth of nano-antioxidants on cellular vesicles for efficient reactive oxygen species elimination in acute inflammatory diseases. NANO TODAY 2021; 40:101282. [DOI: 10.1016/j.nantod.2021.101282] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/23/2023]
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14
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Liedtke K, Alter C, Günther A, Hövelmeyer N, Klopfleisch R, Naumann R, Wunderlich FT, Buer J, Westendorf AM, Hansen W. Endogenous CD83 Expression in CD4 + Conventional T Cells Controls Inflammatory Immune Responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:3217-3226. [PMID: 32341061 DOI: 10.4049/jimmunol.2000042] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/10/2020] [Indexed: 12/16/2022]
Abstract
The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4+Foxp3+ regulatory T cells (Tregs) and CD4+Foxp3- conventional T cells. However, the physiological function of endogenous CD83 in CD4+ T cell subsets is still unclear. In this study, we have generated a new CD83flox mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD83flox/flox/CD4-cretg/wt mice had similar suppressive activity as Tregs from CD83flox/flox/CD4-crewt/wt wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4+ conventional T cells showed elevated proliferation and IFN-γ secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4+ T cell activation. Moreover, adoptive transfer of CD4+CD45RBhigh T cells from CD83flox/flox/CD4-cretg /wt mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c+ dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4+ conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4+ conventional T cells from CD83flox/flox/CD4-crewt/wt wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4+ conventional T cells plays a crucial role in controlling CD4+ T cell responses, at least in part, by regulating the activity of CD11c+ DCs.
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Affiliation(s)
- Katarina Liedtke
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Christina Alter
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Anne Günther
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Nadine Hövelmeyer
- Institute for Medical Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, 55131 Mainz, Germany
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Free University of Berlin, 14163 Berlin, Germany
| | - Ronald Naumann
- Transgenic Core Facility, Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; and
- Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University of Cologne, 50931 Cologne, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany;
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15
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Song W, Li H, Jia B, Wang Z, Liu Q, Yang G, Li X. Soluble CD83 suppresses experimental food allergy via regulating aberrant T helper 2 responses. Immunol Res 2020; 68:141-151. [PMID: 32529460 DOI: 10.1007/s12026-020-09133-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Aberrant T helper-2 (Th2) responses play a critical role in the pathogenesis of allergic diseases. The underlying mechanism is to be further investigated. It is reported that soluble CD83 (sCD83) has immune-regulatory effects. This study aims to investigate the role of sCD83 in the regulation of Th2 polarization. Blood samples were collected from pediatric patients with food allergy (FA). The Th2 response was analyzed by pertinent immunological approaches. An FA murine model was developed to test the role of sCD83 in the regulation of FA response. We found that the serum sCD83 levels were lower in FA patients. A negative correlation was detected between serum sCD83 levels and serum Th2 cytokine levels. The presence of sCD83 suppressed Th2 cell differentiation and antigen-specific Th2 cell activation. sCD83 upregulated the T-bet expression and suppressed the GATA3 expression in CD4+ T cells. Administration of sCD83 suppressed experimental FA. Pediatric FA patients have low serum sCD83 levels. Administration of sCD83 can alleviate experimental FA via suppression of aberrant Th2 polarization.
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Affiliation(s)
- Wenyue Song
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Hongfen Li
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Bingkun Jia
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Zhenxi Wang
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Qingsheng Liu
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Guangping Yang
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China
| | - Xiaorong Li
- Departments of Pediatrics, Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, 158 Minzhu Zhong Road, Jiaozuo, 454150, China.
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16
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Schönberg A, Hamdorf M, Bock F. Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med 2020; 9:E1280. [PMID: 32354200 PMCID: PMC7287922 DOI: 10.3390/jcm9051280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Even though the cornea is regarded as an immune-privileged tissue, transplantation always comes with the risk of rejection due to mismatches between donor and recipient. It is common sense that an alternative to corticosteroids as the current gold standard for treatment of corneal transplantation is needed. Since blood and lymphatic vessels have been identified as a severe risk factor for corneal allograft survival, much research has focused on vessel regression or inhibition of hem- and lymphangiogenesis in general. However, lymphatic vessels have been identified as required for the inflammation's resolution. Therefore, targeting other players of corneal engraftment could reveal new therapeutic strategies. The establishment of a tolerogenic microenvironment at the graft site would leave the recipient with the ability to manage pathogenic conditions independent from transplantation. Dendritic cells (DCs) as the central player of the immune system represent a target that allows the induction of tolerogenic mechanisms by many different strategies. These strategies are reviewed in this article with regard to their success in corneal transplantation.
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Affiliation(s)
- Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Matthias Hamdorf
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
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17
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Grosche L, Knippertz I, König C, Royzman D, Wild AB, Zinser E, Sticht H, Muller YA, Steinkasserer A, Lechmann M. The CD83 Molecule - An Important Immune Checkpoint. Front Immunol 2020; 11:721. [PMID: 32362900 PMCID: PMC7181454 DOI: 10.3389/fimmu.2020.00721] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/30/2020] [Indexed: 12/19/2022] Open
Abstract
The CD83 molecule has been identified to be expressed on numerous activated immune cells, including B and T lymphocytes, monocytes, dendritic cells, microglia, and neutrophils. Both isoforms of CD83, the membrane-bound as well as its soluble form are topic of intensive research investigations. Several studies revealed that CD83 is not a typical co-stimulatory molecule, but rather plays a critical role in controlling and resolving immune responses. Moreover, CD83 is an essential factor during the differentiation of T and B lymphocytes, and the development and maintenance of tolerance. The identification of its interaction partners as well as signaling pathways have been an enigma for the last decades. Here, we report the latest data on the expression, structure, and the signaling partners of CD83. In addition, we review the regulatory functions of CD83, including its striking modulatory potential to maintain the balance between tolerance versus inflammation during homeostasis or pathologies. These immunomodulatory properties of CD83 emphasize its exceptional therapeutic potential, which has been documented in specific preclinical disease models.
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Affiliation(s)
- Linda Grosche
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ilka Knippertz
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christina König
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Yves A. Muller
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias Lechmann
- Department of Immune Modulation, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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18
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Wu YJ, Song YN, Geng XR, Ma F, Mo LH, Zhang XW, Liu DB, Liu ZG, Yang PC. Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property. Int J Biol Sci 2020; 16:216-227. [PMID: 31929750 PMCID: PMC6949156 DOI: 10.7150/ijbs.38722] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 10/15/2019] [Indexed: 11/21/2022] Open
Abstract
Background and aims: Dysfunction of the immune regulatory system plays a role in the pathogenesis of allergic rhinitis (AR). The underlying mechanism needs to be further investigated. Published data indicate that soluble CD83 (sCD83) has immune regulatory activities. This study aims to investigate the role of sCD83 in the alleviation of experimental AR. Methods: Peripheral blood samples were obtained from AR patients. Serum levels of sCD83 were determined by enzyme-linked immunosorbent assay. A murine AR model was developed to test the effects of sCD83 on suppressing experimental AR. Results: We found that serum levels of sCD83 in the AR group were lower than that in the healthy control group. A negative correlation was identified between the serum sCD83 levels and the frequency of T helper-2 (Th2) cells. The low serum sCD83 levels were also associated with the Bcl2L12 expression in antigen-specific Th2 cells. Exposure to sCD83 enhanced the responsiveness of antigen-specific Th2 cells to apoptosis inducers via suppressing the Bcl2L12 expression. Administration of sCD83 efficiently suppressed experimental AR. Conclusions: sCD83 contributes to immune homeostasis by regulating CD4+ T cell activities. Administration of sCD83 may have translational potential for the treatment of AR or other allergic diseases.
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Affiliation(s)
- Yong-Jin Wu
- ENT Hospital of Shenzhen University School of Medicine, Longgang ENT Hospital, Shenzhen, China
| | - Yan-Nan Song
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xiao-Rui Geng
- ENT Hospital of Shenzhen University School of Medicine, Longgang ENT Hospital, Shenzhen, China
| | - Fei Ma
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
- Department of Otolaryngology, Head & Neck Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li-Hua Mo
- Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xiao-Wen Zhang
- Department of Otolaryngology, Head & Neck Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Da-Bo Liu
- Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhi-Gang Liu
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Ping-Chang Yang
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
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19
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Wild AB, Krzyzak L, Peckert K, Stich L, Kuhnt C, Butterhof A, Seitz C, Mattner J, Grüner N, Gänsbauer M, Purtak M, Soulat D, Winkler TH, Nitschke L, Zinser E, Steinkasserer A. CD83 orchestrates immunity toward self and non-self in dendritic cells. JCI Insight 2019; 4:e126246. [PMID: 31527313 PMCID: PMC6824307 DOI: 10.1172/jci.insight.126246] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 09/04/2019] [Indexed: 01/22/2023] Open
Abstract
Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs, although its physiological role is still not completely understood. Using a DC-specific CD83-conditional KO (CD83ΔDC) mouse, we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the costimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83ΔDC mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis model, autoimmune inflammation was dramatically aggravated in CD83ΔDC mice while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83ΔDC mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.
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Affiliation(s)
| | | | | | | | | | | | | | - Jochen Mattner
- Institute of Microbiology — Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Niklas Grüner
- Institute of Microbiology — Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Maximilian Gänsbauer
- Institute of Microbiology — Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Martin Purtak
- Institute of Microbiology — Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Didier Soulat
- Institute of Microbiology — Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas H. Winkler
- Division of Genetics, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lars Nitschke
- Division of Genetics, Department of Biology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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20
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Zinser E, Naumann R, Wild AB, Michalski J, Deinzer A, Stich L, Kuhnt C, Steinkasserer A, Knippertz I. Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells. Front Immunol 2019; 10:1442. [PMID: 31293592 PMCID: PMC6603205 DOI: 10.3389/fimmu.2019.01442] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 06/07/2019] [Indexed: 12/17/2022] Open
Abstract
The CD83 is a type I membrane protein and part of the immunoglobulin superfamily of receptors. CD83 is involved in the regulation of antigen presentation and dendritic cell dependent allogeneic T cell proliferation. A soluble form of CD83 inhibits dendritic cell maturation and function. Furthermore, CD83 is expressed on activated B cells, T cells, and in particular on regulatory T cells. Previous studies on murine CD83 demonstrated this molecule to be involved in several immune-regulatory processes, comprising that CD83 plays a key role in the development und function of different immune cells. In order to get further insights into the function of the human CD83 and to provide preclinical tools to guide the function of CD83/sCD83 for therapeutic purposes we generated Bacterial Artificial Chromosomes (BAC) transgenic mice. BACs are excellent tools for manipulating large DNA fragments and are utilized to engineer transgenic mice by pronuclear injection. Two different founders of BAC transgenic mice expressing human CD83 (BAC-hCD83tg mice) were generated and were examined for the hCD83 expression on different immune cells as well as both the in vitro and in vivo role of human CD83 (hCD83) in health and disease. Here, we found the hCD83 molecule to be present on activated DCs, B cells and subtypes of CD4+ T cells. CD8+ T cells, on the other hand, showed almost no hCD83 expression. To address the function of hCD83, we performed in vitro mixed lymphocyte reactions (MLR) as well as suppression assays and we used the in vivo model of experimental autoimmune encephalomyelitis (EAE) comparing wild-type and hCD83-BAC mice. Results herein showed a clearly diminished capacity of hCD83-BAC-derived T cells to proliferate accompanied by an enhanced activation and suppressive activity of hCD83-BAC-derived Tregs. Furthermore, hCD83-BAC mice were found to recover faster from EAE-associated symptoms than wild-type mice, encouraging the relevance also of the hCD83 as a key molecule for the regulatory phenotype of Tregs in vitro and in vivo.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/immunology
- B-Lymphocytes/immunology
- B-Lymphocytes/pathology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/pathology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Humans
- Immunoglobulins/genetics
- Immunoglobulins/immunology
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/immunology
- Mice
- Mice, Transgenic
- Somatostatin-Secreting Cells/immunology
- Somatostatin-Secreting Cells/pathology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- CD83 Antigen
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Affiliation(s)
- Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ronald Naumann
- Transgenic Core Facility, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Julia Michalski
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andrea Deinzer
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Christine Kuhnt
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | | | - Ilka Knippertz
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
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21
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Li Z, Ju X, Silveira PA, Abadir E, Hsu WH, Hart DNJ, Clark GJ. CD83: Activation Marker for Antigen Presenting Cells and Its Therapeutic Potential. Front Immunol 2019; 10:1312. [PMID: 31231400 PMCID: PMC6568190 DOI: 10.3389/fimmu.2019.01312] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/23/2019] [Indexed: 12/17/2022] Open
Abstract
CD83 is a member of the immunoglobulin (Ig) superfamily and is expressed in membrane bound or soluble forms. Membrane CD83 (mCD83) can be detected on a variety of activated immune cells, although it is most highly and stably expressed by mature dendritic cells (DC). mCD83 regulates maturation, activation and homeostasis. Soluble CD83 (sCD83), which is elevated in the serum of patients with autoimmune disease and some hematological malignancies is reported to have an immune suppressive function. While CD83 is emerging as a promising immune modulator with therapeutic potential, some important aspects such as its ligand/s, intracellular signaling pathways and modulators of its expression are unclear. In this review we discuss the recent biological findings and the potential clinical value of CD83 based therapeutics in various conditions including autoimmune disease, graft-vs.-host disease, transplantation and hematological malignancies.
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Affiliation(s)
- Ziduo Li
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Xinsheng Ju
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Pablo A. Silveira
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Edward Abadir
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Wei-Hsun Hsu
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Derek N. J. Hart
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Georgina J. Clark
- Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
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22
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Royzman D, Andreev D, Stich L, Rauh M, Bäuerle T, Ellmann S, Boon L, Kindermann M, Peckert K, Bozec A, Schett G, Steinkasserer A, Zinser E. Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner. Front Immunol 2019; 10:633. [PMID: 31001257 PMCID: PMC6455294 DOI: 10.3389/fimmu.2019.00633] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 03/08/2019] [Indexed: 12/29/2022] Open
Abstract
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFNγ, IL-6, and TNFα within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-β antibodies further revealed that also TGF-β is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-β dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
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MESH Headings
- Animals
- Antibodies, Blocking/pharmacology
- Antigens, CD/immunology
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/immunology
- Arthritis, Experimental/pathology
- Cytokines/immunology
- Female
- Immunoglobulins/immunology
- Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
- Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology
- Inflammation/drug therapy
- Inflammation/immunology
- Inflammation/pathology
- Joints/immunology
- Joints/pathology
- Membrane Glycoproteins/immunology
- Mice
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Solubility
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- Transforming Growth Factor beta/antagonists & inhibitors
- Transforming Growth Factor beta/immunology
- Tryptophan/analogs & derivatives
- Tryptophan/pharmacology
- CD83 Antigen
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Affiliation(s)
- Dmytro Royzman
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Darja Andreev
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Manfred Rauh
- Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tobias Bäuerle
- Institute of Radiology, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Stephan Ellmann
- Institute of Radiology, Universitätsklinikum Erlangen, Erlangen, Germany
| | | | - Markus Kindermann
- Department of Internal Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katrin Peckert
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany
| | | | - Elisabeth Zinser
- Department of Immune Modulation, Universitätsklinikum Erlangen, Erlangen, Germany
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23
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Pinho MP, Barbuto JAM. Commentary: Soluble CD83 Alleviates Experimental Autoimmune Uveitis by Inhibiting Filamentous Actin-Dependent Calcium Release in Dendritic Cells. Front Immunol 2018; 9:2659. [PMID: 30498498 PMCID: PMC6249379 DOI: 10.3389/fimmu.2018.02659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/29/2018] [Indexed: 11/22/2022] Open
Affiliation(s)
- Mariana Pereira Pinho
- Tumor Immunology Laboratory, Immunology Department, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil
| | - José Alexandre Marzagão Barbuto
- Tumor Immunology Laboratory, Immunology Department, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil
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24
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Lin W, Buscher K, Wang B, Fan Z, Song N, Li P, Yue Y, Li B, Li C, Bi H. Soluble CD83 Alleviates Experimental Autoimmune Uveitis by Inhibiting Filamentous Actin-Dependent Calcium Release in Dendritic Cells. Front Immunol 2018; 9:1567. [PMID: 30050530 PMCID: PMC6052908 DOI: 10.3389/fimmu.2018.01567] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/25/2018] [Indexed: 01/03/2023] Open
Abstract
Soluble CD83 (sCD83) is the extracellular domain of the membrane-bound CD83 molecule, and known for its immunoregulatory functions. Whether and how sCD83 participates in the pathogenesis of uveitis, a serious inflammatory disease of the eye that can cause visual disability and blindness, is unknown. By flow cytometry and imaging studies, we show that sCD83 alleviates experimental autoimmune uveitis (EAU) through a novel mechanism. During onset and recovery of EAU, the level of sCD83 rises in the serum and aqueous humor, and CD83+ leukocytes infiltrate the inflamed eye. Systemic or topical application of sCD83 exerts a protective effect by decreasing inflammatory cytokine expression, reducing ocular and splenic leukocyte including CD4+ T cells and dendritic cells (DCs). Mechanistically, sCD83 induces tolerogenic DCs by decreasing the synaptic expression of co-stimulatory molecules and hampering the calcium response in DCs. These changes are caused by a disruption of the cytoskeletal rearrangements at the DC–T cell contact zone, leading to altered localization of calcium microdomains and suppressed T-cell activation. Thus, the ability of sCD83 to modulate DC-mediated inflammation in the eye could be harnessed to develop new immunosuppressive therapeutics for autoimmune uveitis.
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Affiliation(s)
- Wei Lin
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China.,Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Immunology, Shanghai Medical School, Fudan University, Shanghai, China
| | - Konrad Buscher
- Department of Nephrology and Rheumatology, University Hospital Muenster, Münster, Germany.,Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, United States
| | - Beibei Wang
- Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhichao Fan
- Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, United States
| | - Nannan Song
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Peng Li
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Yingying Yue
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Bingqing Li
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Cuiling Li
- Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, China
| | - Hongsheng Bi
- Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan, China
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25
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Bo L, Guojun T, Li G. An Expanded Neuroimmunomodulation Axis: sCD83-Indoleamine 2,3-Dioxygenase-Kynurenine Pathway and Updates of Kynurenine Pathway in Neurologic Diseases. Front Immunol 2018; 9:1363. [PMID: 29963055 PMCID: PMC6013554 DOI: 10.3389/fimmu.2018.01363] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/01/2018] [Indexed: 12/30/2022] Open
Abstract
Many neurologic diseases are related to autoimmune dysfunction and a variety of molecules or reaction pathways are involved in the regulation of immune function of the nervous system. Soluble CD83 (sCD83) is the soluble form of CD83, a specific marker of mature dendritic cell, which has recently been shown to have an immunomodulatory effect. Indoleamine 2,3-dioxygenase (IDO; corresponding enzyme intrahepatic, tryptophan 2,3-dioxygenase, TDO), a rate-limiting enzyme of extrahepatic tryptophan kynurenine pathway (KP) participates in the immunoregulation through a variety of mechanisms solely or with the synergy of sCD83, and the imbalances of metabolites of KP were associated with immune dysfunction. With the complement of sCD83 to IDO-KP, a previously known immunomodulatory axis, this review focused on an expanded neuroimmunomodulation axis: sCD83-IDO-KP and its involvement in nervous system diseases.
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Affiliation(s)
- Li Bo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Tan Guojun
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guo Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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26
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Doebbeler M, Koenig C, Krzyzak L, Seitz C, Wild A, Ulas T, Baßler K, Kopelyanskiy D, Butterhof A, Kuhnt C, Kreiser S, Stich L, Zinser E, Knippertz I, Wirtz S, Riegel C, Hoffmann P, Edinger M, Nitschke L, Winkler T, Schultze JL, Steinkasserer A, Lechmann M. CD83 expression is essential for Treg cell differentiation and stability. JCI Insight 2018; 3:99712. [PMID: 29875316 PMCID: PMC6124443 DOI: 10.1172/jci.insight.99712] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/01/2018] [Indexed: 12/21/2022] Open
Abstract
Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.
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Affiliation(s)
- Marina Doebbeler
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Christina Koenig
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Lena Krzyzak
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Christine Seitz
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Andreas Wild
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Thomas Ulas
- Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Kevin Baßler
- Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Dmitry Kopelyanskiy
- Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Alina Butterhof
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Christine Kuhnt
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Simon Kreiser
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Ilka Knippertz
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Christin Riegel
- Department of Internal Medicine 3, University Hospital Regensburg, Regensburg, Germany
| | - Petra Hoffmann
- Department of Internal Medicine 3, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Edinger
- Department of Internal Medicine 3, University Hospital Regensburg, Regensburg, Germany
| | - Lars Nitschke
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Winkler
- Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Joachim L. Schultze
- Genomics & Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Matthias Lechmann
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
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27
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Lin W, Man X, Li P, Song N, Yue Y, Li B, Li Y, Sun Y, Fu Q. NK cells are negatively regulated by sCD83 in experimental autoimmune uveitis. Sci Rep 2017; 7:12895. [PMID: 29038541 PMCID: PMC5643513 DOI: 10.1038/s41598-017-13412-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 09/21/2017] [Indexed: 12/17/2022] Open
Abstract
Natural killer (NK) cells represent a subset of lymphocytes that contribute to innate immunity and have been reported to play a role in autoimmune uveitis. However, the mechanisms regulating NK cellular function in this condition remain unclear. Herein, we investigated the status of NK cells in experimental autoimmune uveitis (EAU). We found that the number of CD83+CD3-NK1.1+ cells was increased in the inflamed eyes and spleens of the EAU mouse model. At the recovery stage of EAU, serum concentrations of soluble CD83 (sCD83) were increased. sCD83 treatment relieved retinal tissue damage and decreased the number of infiltrating NK cells in inflamed eyes. Further analysis of the effects of sCD83 treatment in EAU revealed that it reduced: 1) the expressions of CD11b and CD83 in NK cells, 2) the percent of CD11bhighCD27lowCD3-NK1.1+ cells and 3) the secretion of granzyme B, perforin and IFN-γ in NK cells as demonstrated both in vivo and in vitro. When sCD83 treated-NK cells were transferred into EAU mice, retinal tissue damage was relieved. These results demonstrate sCD83 down-regulate NK cellular function and thus provide important, new information regarding the means for the beneficial effects of this agent in the treatment of autoimmune uveitis.
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Affiliation(s)
- Wei Lin
- Department of microbiology, Institute of Basic medicine, Shandong Academy of medical Sciences, Jinan, 250032, China.
| | - Xuejing Man
- Department of Ophthalmology, Yuhuangding Hospital, Yantai, 264001, China
| | - Peng Li
- Department of microbiology, Institute of Basic medicine, Shandong Academy of medical Sciences, Jinan, 250032, China
| | - Nannan Song
- Department of microbiology, Institute of Basic medicine, Shandong Academy of medical Sciences, Jinan, 250032, China
| | - Yingying Yue
- Department of microbiology, Institute of Basic medicine, Shandong Academy of medical Sciences, Jinan, 250032, China
| | - Bingqing Li
- Department of microbiology, Institute of Basic medicine, Shandong Academy of medical Sciences, Jinan, 250032, China
| | - Yuanbin Li
- Department of Ophthalmology, Yuhuangding Hospital, Yantai, 264001, China
| | - Yufei Sun
- Department of Immunology, Binzhou Medical University, Yantai, 264003, China
| | - Qiang Fu
- Department of Immunology, Binzhou Medical University, Yantai, 264003, China.
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28
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Kristensen AM, Stengaard-Pedersen K, Hetland ML, Hørslev-Petersen K, Junker P, Østergaard M, Höllsberg P, Deleuran B, Hvid M. Expression of soluble CD83 in plasma from early-stage rheumatoid arthritis patients is not modified by anti-TNF-α therapy. Cytokine 2017; 96:1-7. [PMID: 28267648 DOI: 10.1016/j.cyto.2017.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/03/2017] [Accepted: 02/17/2017] [Indexed: 01/03/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease which may lead to severe disabilities due to structural joint damage and extraarticular manifestations The dendritic cell marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases. In RA the levels of soluble CD83 (sCD83) are elevated in synovial fluid, however little is known about CD83 expression and regulation in RA. Therefore, we studied how CD83 is expressed in RA and further evaluated the effect of anti-TNF-α therapy hereon. Early RA patients were randomized to conventional disease modifying anti-rheumatic drugs with or without additional anti-TNF-α therapy. Rheumatoid arthritis patients had increased levels of sCD83 in plasma compared with healthy volunteers. The increase in sCD83 plasma levels were unaffected by anti-TNF-α therapy. In chronic RA patients the levels of sCD83 were higher in synovial fluid than in plasma, and only a limited amount of membrane bound CD83 expression was detected on the surface of cells from peripheral blood and synovial fluid. Finally, confocal microscopy of RA synovial membranes revealed that CD83 was mainly localized intracellularly in a group of cells with diverse morphology including both antigen-presenting cells and non-antigen-presenting cells. Our findings demonstrate that early-stage RA patients have elevated levels of sCD83 in plasma and that anti-TNF-α treatment has no effect on the sCD83 plasma level. This suggest that in RA patients sCD83 regulation is beyond control of TNF-α.
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Affiliation(s)
| | - Kristian Stengaard-Pedersen
- Dept. of Rheumatology, Aarhus University Hospital, Denmark; Dept. of Clinical Medicine, Aarhus University, Denmark
| | - Merete Lund Hetland
- The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Kim Hørslev-Petersen
- King Christian 10th Hospital for the Rheumatic Diseases, and University of Southern Denmark, Denmark
| | - Peter Junker
- Dept. of Rheumatology, Odense University Hospital, Denmark
| | - Mikkel Østergaard
- The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | | | - Bent Deleuran
- Dept. of Biomedicine, Aarhus University, Denmark; Dept. of Rheumatology, Aarhus University Hospital, Denmark
| | - Malene Hvid
- Dept. of Biomedicine, Aarhus University, Denmark; Dept. of Clinical Medicine, Aarhus University, Denmark.
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Chiriac MT, Buchen B, Wandersee A, Hundorfean G, Günther C, Bourjau Y, Doyle SE, Frey B, Ekici AB, Büttner C, Weigmann B, Atreya R, Wirtz S, Becker C, Siebler J, Neurath MF. Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease. Gastroenterology 2017; 153:123-138.e8. [PMID: 28342759 DOI: 10.1053/j.gastro.2017.03.015] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. METHODS Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon λ receptor 1 gene (Il28ra-/-), and mice with disruption of the interferon regulatory factor 3 gene (Irf3-/-), with or without disruption of Irf7 (Irf7-/-). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. RESULTS Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 in primary human and mouse IECs, increasing with dose. Il28ra-/-, Irf3-/-, Irf3-/-Irf7-/-, as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra-/- and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. CONCLUSIONS IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD.
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Affiliation(s)
- Mircea T Chiriac
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
| | - Barbara Buchen
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Alexandra Wandersee
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Gheorghe Hundorfean
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Claudia Günther
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Yvonne Bourjau
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | | | - Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Arif B Ekici
- Core Unit Genomics, Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christian Büttner
- Core Unit Genomics, Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Benno Weigmann
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Raja Atreya
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany; Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Stefan Wirtz
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christoph Becker
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jürgen Siebler
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Markus F Neurath
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany; Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany.
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Packhäuser KRH, Roman-Sosa G, Ehrhardt J, Krüger D, Zygmunt M, Muzzio DO. A Kinetic Study of CD83 Reveals an Upregulation and Higher Production of sCD83 in Lymphocytes from Pregnant Mice. Front Immunol 2017; 8:486. [PMID: 28491062 PMCID: PMC5405069 DOI: 10.3389/fimmu.2017.00486] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 04/07/2017] [Indexed: 12/15/2022] Open
Abstract
For the normal development of pregnancy, a balance between immune tolerance and defense is crucial. However, the mechanisms mediating such a balance are not fully understood. CD83 is a transmembrane protein whose expression has been linked to anti-inflammatory functions of T and B cells. The soluble form of CD83, released by cleavage of the membrane-bound protein, has strong anti-inflammatory properties and was successfully tested in different mouse models. It is assumed that this molecule contributes to the establishment of immune tolerance. Therefore, we postulated that the expression of CD83 is crucial for immune tolerance during pregnancy in mice. Here, we demonstrated that the membrane-bound form of CD83 was upregulated in T and B cells during allogeneic murine pregnancies. An upregulation was also evident in the main splenic B cell subtypes: marginal zone, follicular zone, and transitional B cells. We also showed that there was an augmentation in the number of CD83+ cells toward the end of pregnancy within splenic B and CD4+ T cells, while CD83+ dendritic cells were reduced in spleen and inguinal lymph nodes of pregnant mice. Additionally, B lymphocytes in late-pregnancy presented a markedly higher sensitivity to LPS in terms of CD83 expression and sCD83 release. Progesterone induced a dosis-dependent upregulation of CD83 on T cells. Our data suggest that the regulation of CD83 expression represents a novel pathway of fetal tolerance and protection against inflammatory threats during pregnancy.
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Affiliation(s)
| | - Gleyder Roman-Sosa
- Département de Virologie, Unité de Virologie Structurale, Institut Pasteur, Paris, France
| | - Jens Ehrhardt
- Research Laboratory, Department of Obstetrics and Gynecology, University of Greifswald, Greifswald, Germany
| | - Diana Krüger
- Research Laboratory, Department of Obstetrics and Gynecology, University of Greifswald, Greifswald, Germany
| | - Marek Zygmunt
- Research Laboratory, Department of Obstetrics and Gynecology, University of Greifswald, Greifswald, Germany
| | - Damián Oscar Muzzio
- Research Laboratory, Department of Obstetrics and Gynecology, University of Greifswald, Greifswald, Germany
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Heilingloh CS, Klingl S, Egerer-Sieber C, Schmid B, Weiler S, Mühl-Zürbes P, Hofmann J, Stump JD, Sticht H, Kummer M, Steinkasserer A, Muller YA. Crystal Structure of the Extracellular Domain of the Human Dendritic Cell Surface Marker CD83. J Mol Biol 2017; 429:1227-1243. [PMID: 28315353 DOI: 10.1016/j.jmb.2017.03.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 02/10/2017] [Accepted: 03/05/2017] [Indexed: 11/27/2022]
Abstract
CD83 is a type-I membrane protein and an efficient marker for identifying mature dendritic cells. Whereas membrane-bound, full-length CD83 co-stimulates the immune system, a soluble variant (sCD83), consisting of the extracellular domain only, displays strong immune-suppressive activities. Besides a prediction that sCD83 adopts a V-set Ig-like fold, however, little is known about the molecular architecture of CD83 and the mechanism by which CD83 exerts its function on dendritic cells and additional immune cells. Here, we report the crystal structure of human sCD83 up to a resolution of 1.7Å solved in three different crystal forms. Interestingly, β-strands C', C″, and D that are typical for V-set Ig-domains could not be traced in sCD83. Mass spectrometry analyses, limited proteolysis experiments, and bioinformatics studies show that the corresponding segment displays enhanced main-chain accessibility, extraordinary low sequence conservation, and a predicted high disorder propensity. Chimeric proteins with amino acid swaps in this segment show unaltered immune-suppressive activities in a TNF-α assay when compared to wild-type sCD83. This strongly indicates that this segment does not participate in the biological activity of CD83. The crystal structure of CD83 shows the recurrent formation of dimers and trimers in the various crystal forms and reveals strong structural similarities between sCD83 and B7 family members and CD48, a signaling lymphocyte activation molecule family member. This suggests that CD83 exerts its immunological activity by mixed homotypic and heterotypic interactions as typically observed for proteins present in the immunological synapse.
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Affiliation(s)
- Christiane S Heilingloh
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, D-91052 Erlangen, Germany
| | - Stefan Klingl
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Henkestr. 91, D-91052 Erlangen, Germany
| | - Claudia Egerer-Sieber
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Henkestr. 91, D-91052 Erlangen, Germany
| | - Benedikt Schmid
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Henkestr. 91, D-91052 Erlangen, Germany
| | - Sigrid Weiler
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Henkestr. 91, D-91052 Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, D-91052 Erlangen, Germany
| | - Jörg Hofmann
- Division of Biochemistry, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Staudtstr. 5, D-91058 Erlangen, Germany
| | - Joachim D Stump
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstraße 17, D-91054 Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstraße 17, D-91054 Erlangen, Germany
| | - Mirko Kummer
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, D-91052 Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, D-91052 Erlangen, Germany
| | - Yves A Muller
- Division of Biotechnology, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Henkestr. 91, D-91052 Erlangen, Germany.
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32
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Horvatinovich JM, Grogan EW, Norris M, Steinkasserer A, Lemos H, Mellor AL, Tcherepanova IY, Nicolette CA, DeBenedette MA. Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14 + Monocytes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 198:2286-2301. [PMID: 28193829 PMCID: PMC5337811 DOI: 10.4049/jimmunol.1600802] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 01/13/2017] [Indexed: 12/17/2022]
Abstract
The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R-associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2-dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.
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Affiliation(s)
| | | | - Marcus Norris
- Research Department, Argos Therapeutics, Inc., Durham, NC 27704
| | - Alexander Steinkasserer
- Cancer Immunology, Department of Immune Modulation, University Hospital Erlangen, University of Erlangen-Nuremberg, D-91052 Erlangen, Germany; and
| | - Henrique Lemos
- Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912
| | - Andrew L Mellor
- Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912
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33
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Heilingloh CS, Grosche L, Kummer M, Mühl-Zürbes P, Kamm L, Scherer M, Latzko M, Stamminger T, Steinkasserer A. The Major Immediate-Early Protein IE2 of Human Cytomegalovirus Is Sufficient to Induce Proteasomal Degradation of CD83 on Mature Dendritic Cells. Front Microbiol 2017; 8:119. [PMID: 28203230 PMCID: PMC5285329 DOI: 10.3389/fmicb.2017.00119] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 01/17/2017] [Indexed: 01/03/2023] Open
Abstract
Human cytomegalovirus (HCMV) is the prototypic beta-herpesvirus and widespread throughout the human population. While infection is asymptomatic in healthy individuals, it can lead to high morbidity and mortality in immunocompromised persons. Importantly, HCMV evolved multiple strategies to interfere with immune cell function in order to establish latency in infected individuals. As mature DCs (mDCs) are antigen-presenting cells able to activate naïve T cells they play a crucial role during induction of effective antiviral immune responses. Interestingly, earlier studies demonstrated that the functionally important mDC surface molecule CD83 is down-regulated upon HCMV infection resulting in a reduced T cell stimulatory capacity of the infected cells. However, the viral effector protein and the precise mechanism of HCMV-mediated CD83 reduction remain to be discovered. Using flow cytometric analyses, we observed significant down-modulation of CD83 surface expression becoming significant already 12 h after HCMV infection. Moreover, Western bot analyses revealed that, in sharp contrast to previous studies, loss of CD83 is not restricted to the membrane-bound molecule, but also occurs intracellularly. Furthermore, inhibition of the proteasome almost completely restored CD83 surface expression during HCMV infection. Results of infection kinetics and cycloheximide-actinomycin D-chase experiments, strongly suggested that an HCMV immediate early gene product is responsible for the induction of CD83 down-modulation. Consequently, we were able to identify the major immediate early protein IE2 as the viral effector protein that induces proteasomal CD83 degradation.
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Affiliation(s)
| | - Linda Grosche
- Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany
| | - Mirko Kummer
- Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany
| | - Lisa Kamm
- Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany
| | - Myriam Scherer
- Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg Erlangen, Germany
| | - Melanie Latzko
- Department of Immune Modulation, University Hospital Erlangen Erlangen, Germany
| | - Thomas Stamminger
- Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg Erlangen, Germany
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Ju X, Silveira PA, Hsu WH, Elgundi Z, Alingcastre R, Verma ND, Fromm PD, Hsu JL, Bryant C, Li Z, Kupresanin F, Lo TH, Clarke C, Lee K, McGuire H, Fazekas de St Groth B, Larsen SR, Gibson J, Bradstock KF, Clark GJ, Hart DNJ. The Analysis of CD83 Expression on Human Immune Cells Identifies a Unique CD83+-Activated T Cell Population. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 197:4613-4625. [PMID: 27837105 DOI: 10.4049/jimmunol.1600339] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 10/10/2016] [Indexed: 02/02/2023]
Abstract
CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4+, CD8+ T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
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Affiliation(s)
- Xinsheng Ju
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
| | - Pablo A Silveira
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Wei-Hsun Hsu
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Zehra Elgundi
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
| | - Renz Alingcastre
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
| | - Nirupama D Verma
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
| | - Phillip D Fromm
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Jennifer L Hsu
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Institute of Haematology, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, Australia
| | - Christian Bryant
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Institute of Haematology, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, Australia
| | - Ziduo Li
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Fiona Kupresanin
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
| | - Tsun-Ho Lo
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Candice Clarke
- Anatomical Pathology Department, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia; and
| | - Kenneth Lee
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
- Anatomical Pathology Department, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia; and
| | - Helen McGuire
- Centenary Institute, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia
| | | | - Stephen R Larsen
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
- Institute of Haematology, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, Australia
| | - John Gibson
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
- Institute of Haematology, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales 2050, Australia
| | - Kenneth F Bradstock
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Georgina J Clark
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
| | - Derek N J Hart
- ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia;
- Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia
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von Rohrscheidt J, Petrozziello E, Nedjic J, Federle C, Krzyzak L, Ploegh HL, Ishido S, Steinkasserer A, Klein L. Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83. J Exp Med 2016; 213:1685-94. [PMID: 27503071 PMCID: PMC4995086 DOI: 10.1084/jem.20160316] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/10/2016] [Indexed: 01/12/2023] Open
Abstract
Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and -extrinsic functions through discrete protein domains, but it remains unclear how CD83's capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83's transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83(-/-) mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83's TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83(-/-) mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.
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Affiliation(s)
- Julia von Rohrscheidt
- Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany
| | - Elisabetta Petrozziello
- Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany
| | - Jelena Nedjic
- Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany
| | - Christine Federle
- Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany
| | - Lena Krzyzak
- Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany
| | - Hidde L Ploegh
- Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142
| | - Satoshi Ishido
- Department of Microbiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
| | | | - Ludger Klein
- Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany
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Krzyzak L, Seitz C, Urbat A, Hutzler S, Ostalecki C, Gläsner J, Hiergeist A, Gessner A, Winkler TH, Steinkasserer A, Nitschke L. CD83 Modulates B Cell Activation and Germinal Center Responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 196:3581-94. [PMID: 26983787 DOI: 10.4049/jimmunol.1502163] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 02/18/2016] [Indexed: 12/16/2023]
Abstract
CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo.
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Affiliation(s)
- Lena Krzyzak
- Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany
| | - Christine Seitz
- Department of Immune Modulation, University Hospital Erlangen, 91052 Erlangen, Germany
| | - Anne Urbat
- Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany
| | - Stefan Hutzler
- Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany
| | - Christian Ostalecki
- Department of Dermatology, University Hospital Erlangen, 91052 Erlangen, Germany
| | - Joachim Gläsner
- Institute for Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany; and
| | - Andreas Hiergeist
- Institute for Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany; and
| | - André Gessner
- Institute for Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany; and
| | - Thomas H Winkler
- Division of Genetics, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen, 91058 Erlangen, Germany
| | | | - Lars Nitschke
- Division of Genetics, Department of Biology, University of Erlangen, 91058 Erlangen, Germany;
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Heilingloh CS, Kummer M, Mühl-Zürbes P, Drassner C, Daniel C, Klewer M, Steinkasserer A. L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation. J Virol 2015; 89:11046-55. [PMID: 26311871 PMCID: PMC4621140 DOI: 10.1128/jvi.01517-15] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/19/2015] [Indexed: 01/11/2023] Open
Abstract
UNLABELLED Mature dendritic cells (mDCs) are known as the most potent antigen-presenting cells (APCs) since they are also able to prime/induce naive T cells. Thus, mDCs play a pivotal role during the induction of antiviral immune responses. Remarkably, the cell surface molecule CD83, which was shown to have costimulatory properties, is targeted by herpes simplex virus 1 (HSV-1) for viral immune escape. Infection of mDCs with HSV-1 results in downmodulation of CD83, resulting in reduced T cell stimulation. In this study, we report that not only infected mDCs but also uninfected bystander cells in an infected culture show a significant CD83 reduction. We demonstrate that this effect is independent of phagocytosis and transmissible from infected to uninfected mDCs. The presence of specific viral proteins found in these uninfected bystander cells led to the hypothesis that viral proteins are transferred from infected to uninfected cells via L particles. These L particles are generated during lytic replication in parallel with full virions, called H particles. L particles contain viral proteins but lack the viral capsid and DNA. Therefore, these particles are not infectious but are able to transfer several viral proteins. Incubation of mDCs with L particles indeed reduced CD83 expression on uninfected bystander DCs, providing for the first time evidence that functional viral proteins are transmitted via L particles from infected mDCs to uninfected bystander cells, thereby inducing CD83 downmodulation. IMPORTANCE HSV-1 has evolved a number of strategies to evade the host's immune system. Among others, HSV-1 infection of mDCs results in an inhibited T cell activation caused by degradation of CD83. Interestingly, CD83 is lost not only from HSV-1-infected mDCs but also from uninfected bystander cells. The release of so-called L particles, which contain several viral proteins but lack capsid and DNA, during infection is a common phenomenon observed among several viruses, such as human cytomegalovirus (HCMV), Epstein-Barr virus, and HSV-1. However, the detailed function of these particles is poorly understood. Here, we provide for the first time evidence that functional viral proteins can be transferred to uninfected bystander mDCs via L particles, revealing important biological functions of these particles during lytic replication. Therefore, the transfer of viral proteins by L particles to modulate uninfected bystander cells may represent an additional strategy for viral immune escape.
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Affiliation(s)
| | - Mirko Kummer
- Department of Immune Modulation, University Hospital Erlangen, Erlangen, Germany
| | - Petra Mühl-Zürbes
- Department of Immune Modulation, University Hospital Erlangen, Erlangen, Germany
| | - Christina Drassner
- Department of Immune Modulation, University Hospital Erlangen, Erlangen, Germany
| | - Christoph Daniel
- Department of Pathology, Nephropathology, University Hospital Erlangen, Erlangen, Germany
| | - Monika Klewer
- Department of Pathology, Nephropathology, University Hospital Erlangen, Erlangen, Germany
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CHEN LIWEN, GUAN SHIHE, ZHOU QIANG, SHENG SHOUQIN, ZHONG FEI, WANG QIN. Continuous expression of CD83 on activated human CD4⁺ T cells is correlated with their differentiation into induced regulatory T cells. Mol Med Rep 2015; 12:3309-3314. [PMID: 25997495 PMCID: PMC4526085 DOI: 10.3892/mmr.2015.3796] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 04/15/2015] [Indexed: 11/19/2022] Open
Abstract
CD83 is a widely recognized surface marker for mature dendritic cells, which are essential for priming naïve CD4+ T cells into effector cells. However, CD83 is also expressed on activated CD4+ T cells, which remains an enigma in T‑cell mediated immunity. Therefore, the identification of the biological features and regulation of the expression of CD83 on activated CD4+ T cells is important in understanding the function of CD83 in the adaptive immune response. The present study revealed a time‑dependent manner of the expression of CD83 on anti‑CD3/CD28‑stimulated human CD4+ T cells, which is characterized by the maximum expression at day 2 and a significant decrease at day 3. The reduced expression is not a result of a reduced rate of cell proliferation. The activation of interleukin‑2 and secretion of interferon‑γ accumulated progressively from day 1 to 3. Of note, sustained expression of CD83 was observed when CD4+ T cells were induced by transforming growth factor-β to differentiate into CD4+CD25+ forkhead box P3+ regulatory T (iTreg) cells. Confocal immunofluorescence microscopy analysis demonstrated that CD83 was highly co‑localized with CD25 on activated CD4+ T cells. In conclusion, the findings of the present study suggested that the continuous expression of CD83 on activated human CD4+ T cells is correlated with their differentiation into iTreg cells.
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Affiliation(s)
- LIWEN CHEN
- Departments of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - SHIHE GUAN
- Departments of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - QIANG ZHOU
- Departments of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - SHOUQIN SHENG
- Medical Research Center, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - FEI ZHONG
- Department of Medical Oncology, The First Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - QIN WANG
- Departments of Laboratory Medicine, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
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Cao X, Liu M, Wang P, Liu DY. Intestinal dendritic cells change in number in fulminant hepatic failure. World J Gastroenterol 2015; 21:4883-4893. [PMID: 25945001 PMCID: PMC4408460 DOI: 10.3748/wjg.v21.i16.4883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 11/12/2014] [Accepted: 01/16/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the change in intestinal dendritic cell (DC) number in fulminant hepatic failure (FHF).
METHODS: An animal model of FHF was created. Intestinal CD11b/c was detected by immunohistochemistry and Western blot. Quantitative real-time polymerase chain reaction (PCR) was used to detect intestinal integrin-α mRNA expression. Intestinal CD83, CD86, CD74, CD3 and AKT were detected by immunohistochemistry, Western blot and PCR. Phosphorylated-AKT (p-AKT) was detected by immunohistochemistry and Western blot.
RESULTS: In the FHF group [D-galactosamine (D-Galn) + lipopolysaccharide (LPS) group], the mice began to die after 6 h; conversely, in the D-Galn and LPS groups, the activity of mice was poor, but there were no deaths. Immunohistochemistry results showed that in FHF, the expression of CD11b/c (7988400 ± 385941 vs 1102400 ± 132273, P < 0.05), CD83 (13875000 ± 467493 vs 9257600 ± 400364, P < 0.05), CD86 (7988400 ± 385941 vs 1102400 ± 13227, P < 0.05) and CD74 (11056000 ± 431427 vs 4633400 ± 267903, P < 0.05) was significantly increased compared with the normal saline (NS) group. Compared with the NS group, the protein expression of CD11b/c (5.4817 ± 0.77 vs 1.4073 ± 0.37, P < 0.05) and CD86 (4.2673 ± 0.69 vs 1.1379 ± 0.42, P < 0.05) was significantly increased. Itg-α (1.1224 ± 0.3 vs 0.4907 ± 0.19, P < 0.05), CD83 (3.6986 ± 0.40 vs 1.0762 ± 0.22, P < 0.05) and CD86 (1.5801 ± 0.32 vs 0.8846 ± 0.10, P < 0.05) mRNA expression was increased significantly in the FHF group. At the protein level, expression of CD74 in the FHF group (2.3513 ± 0.52) was significantly increased compared with the NS group (1.1298 ± 0.33), whereas in the LPS group (2.3891 ± 0.47), the level of CD74 was the highest (P < 0.05). At the gene level, the relative expression of CD74 mRNA in the FHF group (1.5383 ± 0.26) was also significantly increased in comparison to the NS group (0.7648 ± 0.22; P < 0.05). CD3 expression was the highest in the FHF group (P < 0.05). In the FHF, LPS and D-Galn groups, the expression of AKT at the protein and mRNA levels was elevated compared with the NS group, but there was no statistical significance (P > 0.05). The p-AKT protein expression in the FHF (1.54 ± 0.06), LPS (1.56 ± 0.05) and D-Galn (1.29 ± 0.03) groups was higher than that in the NS group (1.07 ± 0.03) (P < 0.05).
CONCLUSION: In FHF, a large number of DCs mature, express CD86, and activate MHC class II molecular pathways to induce a T cell response, and the AKT pathway is activated.
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Kreiser S, Eckhardt J, Kuhnt C, Stein M, Krzyzak L, Seitz C, Tucher C, Knippertz I, Becker C, Günther C, Steinkasserer A, Lechmann M. Murine CD83-positive T cells mediate suppressor functions in vitro and in vivo. Immunobiology 2015; 220:270-9. [PMID: 25151500 DOI: 10.1016/j.imbio.2014.08.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 07/22/2014] [Accepted: 08/04/2014] [Indexed: 10/24/2022]
Abstract
The CD83 molecule (CD83) is a well-known surface marker present on mature dendritic cells (mDC). In this study, we show that CD83 is also expressed on a subset of T cells which mediate regulatory T cell (Treg)-like suppressor functions in vitro and in vivo. Treg-associated molecules including CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4), glucocorticoid-induced TNFR family-related gene (GITR), Helios and neuropilin-1 (NRP-1) as well as forkhead box protein 3 (FOXP3) were specifically expressed by these CD83(+) T cells. In contrast, CD83(-) T cells showed a naive T cell phenotype with effector T cell properties upon activation. Noteworthy, CD83(-) T cells were not able to upregulate CD83 despite activation. Furthermore, CD83(+) T cells suppressed the proliferation and inflammatory cytokine release of CD83(-) T cells in vitro. Strikingly, stimulated CD83(+) T cells released soluble CD83 (sCD83), which has been reported to possess immunosuppressive properties. In vivo, using the murine transfer colitis model we could show that CD83(+) T cells were able to suppress colitis symptoms while CD83(-) T cells possessed effector functions. In addition, this CD83 expression is also conserved on expanded human Treg. Thus, from these studies we conclude that CD83(+) T cells share important features with regulatory T cells, identifying CD83 as a novel lineage marker to discriminate between different T cell populations.
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Affiliation(s)
- Simon Kreiser
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Jenny Eckhardt
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Christine Kuhnt
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Marcello Stein
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Lena Krzyzak
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Christine Seitz
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Christine Tucher
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Ilka Knippertz
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Christoph Becker
- Department of Medicine 1, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Claudia Günther
- Department of Medicine 1, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany
| | - Matthias Lechmann
- Department of Immune Modulation at the Department of Dermatology, University Hospital Erlangen, Erlangen D-91052, Germany; Department of Medicine 1, University Hospital Erlangen, Erlangen D-91052, Germany.
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