A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4


Journal

Mucosal immunology
ISSN: 1935-3456
Titre abrégé: Mucosal Immunol
Pays: United States
ID NLM: 101299742

Informations de publication

Date de publication:
03 2022
Historique:
received: 14 07 2021
accepted: 19 01 2022
revised: 10 01 2022
pubmed: 17 2 2022
medline: 28 4 2022
entrez: 16 2 2022
Statut: ppublish

Résumé

Immunosuppressive Interleukin (IL)-10 production by pro-inflammatory CD4

Identifiants

pubmed: 35169232
doi: 10.1038/s41385-022-00487-x
pii: S1933-0219(22)00069-1
pmc: PMC9038525
doi:

Substances chimiques

Maf protein, mouse 0
Proto-Oncogene Proteins c-maf 0
STAT3 Transcription Factor 0
STAT3 protein, human 0
Interleukin-10 130068-27-8

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

480-490

Informations de copyright

© 2022. The Author(s).

Références

Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O’Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).
pubmed: 11244051 doi: 10.1146/annurev.immunol.19.1.683
Neumann, C., Scheffold, A. & Rutz, S. Functions and regulation of T cell-derived interleukin-10. Semin Immunol. 44, 101344 (2019).
pubmed: 31727465 doi: 10.1016/j.smim.2019.101344
Engelhardt, K. R. & Grimbacher, B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr. Top. Microbiol Immunol. 380, 1–18 (2014).
pubmed: 25004811
Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).
pubmed: 8402911 doi: 10.1016/0092-8674(93)80068-P
Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).
pubmed: 21166540 doi: 10.1146/annurev-immunol-031210-101312
Roers, A. et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J. Exp. Med 200, 1289–1297 (2004).
pubmed: 15534372 pmcid: 2211912 doi: 10.1084/jem.20041789
Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).
pubmed: 18387831 doi: 10.1016/j.immuni.2008.02.017
Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med 190, 995–1004 (1999).
pubmed: 10510089 pmcid: 2195650 doi: 10.1084/jem.190.7.995
Vieira, P. L. et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172, 5986–5993 (2004).
pubmed: 15128781 doi: 10.4049/jimmunol.172.10.5986
Roncarolo, M. G., Gregori, S., Bacchetta, R., Battaglia, M. & Gagliani, N. The biology of T regulatory type 1 cells and their therapeutic application in immune-mediated diseases. Immunity 49, 1004–1019 (2018).
pubmed: 30566879 doi: 10.1016/j.immuni.2018.12.001
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).
pubmed: 9338786 doi: 10.1038/39614
Jankovic, D. et al. Conventional T-bet(+)Foxp3(−) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med 204, 273–283 (2007).
pubmed: 17283209 pmcid: 2118735 doi: 10.1084/jem.20062175
Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med 204, 285–297 (2007).
pubmed: 17283207 pmcid: 2118728 doi: 10.1084/jem.20061886
Jankovic, D., Kugler, D. G. & Sher, A. IL-10 production by CD4+ effector T cells: a mechanism for self-regulation. Mucosal Immunol. 3, 239–246 (2010).
pubmed: 20200511 pmcid: 4105209 doi: 10.1038/mi.2010.8
Trinchieri, G. Interleukin-10 production by effector T cells: Th1 cells show self control. J. Exp. Med 204, 239–243 (2007).
pubmed: 17296790 pmcid: 2118719 doi: 10.1084/jem.20070104
O’Garra, A. & Vieira, P. T(H)1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).
pubmed: 17525751 doi: 10.1038/nri2097
Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009).
pubmed: 19646904 pmcid: 2791889 doi: 10.1016/j.immuni.2009.05.012
Chang, H. D. et al. Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur. J. Immunol. 37, 807–817 (2007).
pubmed: 17304625 doi: 10.1002/eji.200636385
McGeachy, M. J. et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).
pubmed: 17994024 doi: 10.1038/ni1539
Spolski, R., Kim, H. P., Zhu, W., Levy, D. E. & Leonard, W. J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009).
pubmed: 19234181 doi: 10.4049/jimmunol.0802978
Ghoreschi, K. et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467, 967–971 (2010).
pubmed: 20962846 pmcid: 3108066 doi: 10.1038/nature09447
Batten, M. et al. Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol. 180, 2752–2756 (2008).
pubmed: 18292493 doi: 10.4049/jimmunol.180.5.2752
Stumhofer, J. S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).
pubmed: 17994025 doi: 10.1038/ni1537
Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).
pubmed: 17994022 doi: 10.1038/ni1541
Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797–801 (2009).
pubmed: 19570826 doi: 10.4049/jimmunol.0901233
Fitzgerald, D. C. et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat. Immunol. 8, 1372–1379 (2007).
pubmed: 17994023 doi: 10.1038/ni1540
Zhang, H. et al. An IL-27-driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets. Cell Rep. 33, 108433 (2020).
pubmed: 33238123 pmcid: 7771052 doi: 10.1016/j.celrep.2020.108433
Levings, M. K. et al. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166, 5530–5539 (2001).
pubmed: 11313392 doi: 10.4049/jimmunol.166.9.5530
Ziegler-Heitbrock, L. et al. IFN-alpha induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol. 171, 285–290 (2003).
pubmed: 12817009 doi: 10.4049/jimmunol.171.1.285
Aman, M. J. et al. Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes. Blood 87, 4731–4736 (1996).
pubmed: 8639843 doi: 10.1182/blood.V87.11.4731.bloodjournal87114731
Corre, B. et al. Type I interferon potentiates T-cell receptor mediated induction of IL-10-producing CD4(+) T cells. Eur. J. Immunol. 43, 2730–2740 (2013).
pubmed: 23839924 doi: 10.1002/eji.201242977
Rutz, S. et al. Notch regulates IL-10 production by T helper 1 cells. Proc. Natl Acad. Sci. USA 105, 3497–3502 (2008).
pubmed: 18292228 pmcid: 2265185 doi: 10.1073/pnas.0712102105
Kassner, N. et al. Cutting edge: plasmacytoid dendritic cells induce IL-10 production in T cells via the delta-like-4/Notch axis. J. Immunol. 184, 550–554 (2010).
pubmed: 20008296 doi: 10.4049/jimmunol.0903152
Neumann, K. et al. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway. Eur. J. Immunol. 45, 2008–2016 (2015).
pubmed: 25884798 doi: 10.1002/eji.201445346
Neumann, C. et al. Role of Blimp-1 in programing Th effector cells into IL-10 producers. J. Exp. Med 211, 1807–1819 (2014).
pubmed: 25073792 pmcid: 4144744 doi: 10.1084/jem.20131548
Imbratta, C., Hussein, H., Andris, F. & Verdeil, G. c-MAF, a swiss army knife for tolerance in lymphocytes. Front Immunol. 11, 206 (2020).
pubmed: 32117317 pmcid: 7033575 doi: 10.3389/fimmu.2020.00206
Gabrysova, L. et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells. Nat. Immunol. 19, 497–507 (2018).
pubmed: 29662170 pmcid: 5988041 doi: 10.1038/s41590-018-0083-5
Neumann, C. et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis. Nat. Immunol. 20, 471–481 (2019).
pubmed: 30778241 doi: 10.1038/s41590-019-0316-2
Parish, I. A. et al. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J. Clin. Invest 124, 3455–3468 (2014).
pubmed: 25003188 pmcid: 4109559 doi: 10.1172/JCI66108
Iwasaki, Y. et al. Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. Eur. J. Immunol. 43, 1063–1073 (2013).
pubmed: 23349024 doi: 10.1002/eji.201242942
Xu, J. et al. c-Maf regulates IL-10 expression during Th17 polarization. J. Immunol. 182, 6226–6236 (2009).
pubmed: 19414776 doi: 10.4049/jimmunol.0900123
Martins, G. A. et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 (2006).
pubmed: 16565721 doi: 10.1038/ni1320
Cretney, E. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12, 304–311 (2011).
pubmed: 21378976 doi: 10.1038/ni.2006
Aschenbrenner, D. et al. An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat. Immunol. 19, 1126–1136 (2018).
pubmed: 30201991 pmcid: 6402560 doi: 10.1038/s41590-018-0200-5
Perucha, E. et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat. Commun. 10, 498 (2019).
pubmed: 30700717 pmcid: 6353904 doi: 10.1038/s41467-019-08332-9
Jin, J. O., Han, X. & Yu, Q. Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. J. Autoimmun. 40, 28–44 (2013).
pubmed: 22921334 doi: 10.1016/j.jaut.2012.07.009
Duhen, T., Duhen, R., Lanzavecchia, A., Sallusto, F. & Campbell, D. J. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119, 4430–4440 (2012).
pubmed: 22438251 pmcid: 3362361 doi: 10.1182/blood-2011-11-392324
Tu, L. et al. Notch signaling is an important regulator of type 2 immunity. J. Exp. Med 202, 1037–1042 (2005).
pubmed: 16230473 pmcid: 2213210 doi: 10.1084/jem.20050923
Kamali, A. N. et al. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol. Immunol. 105, 107–115 (2019).
pubmed: 30502718 doi: 10.1016/j.molimm.2018.11.015
Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44, 989–1004 (2016).
pubmed: 27192565 pmcid: 4942846 doi: 10.1016/j.immuni.2016.05.001
Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med 19, 739–746 (2013).
pubmed: 23624599 doi: 10.1038/nm.3179
Gabrysova, L., Howes, A., Saraiva, M. & O’Garra, A. The regulation of IL-10 expression. Curr. Top. Microbiol Immunol. 380, 157–190 (2014).
pubmed: 25004818
Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).
pubmed: 20154735 doi: 10.1038/nri2711
Benson, R. A. et al. Notch1 co-localizes with CD4 on activated T cells and Notch signaling is required for IL-10 production. Eur. J. Immunol. 35, 859–869 (2005).
pubmed: 15688350 doi: 10.1002/eji.200425562
Le Friec, G. et al. The CD46-Jagged1 interaction is critical for human TH1 immunity. Nat. Immunol. 13, 1213–1221 (2012).
pubmed: 23086448 pmcid: 3505834 doi: 10.1038/ni.2454
Mitchell, R. E. et al. IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci. Rep. 7, 11315 (2017).
pubmed: 28900244 pmcid: 5595963 doi: 10.1038/s41598-017-11803-y
Avalle, L., Pensa, S., Regis, G., Novelli, F. & Poli, V. STAT1 and STAT3 in tumorigenesis: A matter of balance. JAKSTAT 1, 65–72 (2012).
pubmed: 24058752 pmcid: 3670295
Regis, G., Pensa, S., Boselli, D., Novelli, F. & Poli, V. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev. Biol. 19, 351–359 (2008).
pubmed: 18620071 doi: 10.1016/j.semcdb.2008.06.004
Qing, Y. & Stark, G. R. Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J. Biol. Chem. 279, 41679–41685 (2004).
pubmed: 15284232 doi: 10.1074/jbc.M406413200
Wan, C. K. et al. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc. Natl Acad. Sci. USA 112, 9394–9399 (2015).
pubmed: 26170288 pmcid: 4522759 doi: 10.1073/pnas.1511711112
Hong, F. et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J. Clin. Invest 110, 1503–1513 (2002).
pubmed: 12438448 pmcid: 151811 doi: 10.1172/JCI0215841
Murano, T. et al. Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells. Biochem Biophys. Res. Commun. 443, 840–846 (2014).
pubmed: 24342613 doi: 10.1016/j.bbrc.2013.12.061
Zhou, X. et al. Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity. Stem Cells 31, 1511–1522 (2013).
pubmed: 23649667 pmcid: 4063271 doi: 10.1002/stem.1426
Kamakura, S. et al. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat. Cell Biol. 6, 547–554 (2004).
pubmed: 15156153 doi: 10.1038/ncb1138
Zhang, P. et al. Eomesodermin promotes the development of type 1 regulatory T (TR1) cells. Sci. Immunol. 2, https://doi.org/10.1126/sciimmunol.aah7152 (2017).
Gruarin, P. et al. Eomesodermin controls a unique differentiation program in human IL-10 and IFN-gamma coproducing regulatory T cells. Eur. J. Immunol. 49, 96–111 (2019).
pubmed: 30431161 doi: 10.1002/eji.201847722
Bonnal, R. J. P. et al. Clonally expanded EOMES(+) Tr1-like cells in primary and metastatic tumors are associated with disease progression. Nat. Immunol. 22, 735–745 (2021).
pubmed: 34017124 doi: 10.1038/s41590-021-00930-4
Yadava, K. et al. Natural Tr1-like cells do not confer long-term tolerogenic memory. Elife 8, https://doi.org/10.7554/eLife.44821 (2019).
Alfen, J. S. et al. Intestinal IFN-gamma-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease. J. Allergy Clin. Immunol. 142, 1537–1547 e1538 (2018).
pubmed: 29369775 doi: 10.1016/j.jaci.2017.12.984
Brockmann, L. et al. Molecular and functional heterogeneity of IL-10-producing CD4(+) T cells. Nat. Commun. 9, 5457 (2018).
pubmed: 30575716 pmcid: 6303294 doi: 10.1038/s41467-018-07581-4
Chihara, N. et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558, 454–459 (2018).
pubmed: 29899446 pmcid: 6130914 doi: 10.1038/s41586-018-0206-z
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
pubmed: 23128233 pmcid: 3491803 doi: 10.1038/nature11582
Zhang, J. et al. Associations between STAT3 rs744166 polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: a meta-analysis. PLoS One 9, e109625 (2014).
pubmed: 25286337 pmcid: 4186844 doi: 10.1371/journal.pone.0109625
Ellinghaus, D. et al. Association between variants of PRDM1 and NDP52 and Crohn’s disease, based on exome sequencing and functional studies. Gastroenterology 145, 339–347 (2013).
pubmed: 23624108 doi: 10.1053/j.gastro.2013.04.040
Galvez, J. Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm. 2014, 928461 (2014).
pubmed: 25101191 pmcid: 4005031 doi: 10.1155/2014/928461
Harbour, S. N., Maynard, C. L., Zindl, C. L., Schoeb, T. R. & Weaver, C. T. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc. Natl. Acad. Sci. USA 112, 7061–7066 (2015).
pubmed: 26038559 pmcid: 4460486 doi: 10.1073/pnas.1415675112
Monteleone, I., Pallone, F. & Monteleone, G. Th17-related cytokines: new players in the control of chronic intestinal inflammation. BMC Med. 9, 122 (2011).
pubmed: 22082127 pmcid: 3239315 doi: 10.1186/1741-7015-9-122
Giles, E. M. et al. Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. Mucosal. Immunol. 10, 184–193 (2017).
pubmed: 27220814 doi: 10.1038/mi.2016.44

Auteurs

Jonas Ahlers (J)

Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Sanofi Pasteur, Sanofi-Aventis Deutschland GmbH, Berlin, Germany.

Andrej Mantei (A)

Labor Berlin, Charité Vivantes GmbH, Berlin, Germany.

Laura Lozza (L)

Cell Biology, Precision for Medicine GmbH, Berlin, Germany.

Manuela Stäber (M)

Central Lab Service, Max-Plack-Institute for Infection Biology, Berlin, Germany.

Frederik Heinrich (F)

German Rheumatism Research Center (DRFZ) Berlin, Leibniz Association, Berlin, Germany.

Petra Bacher (P)

Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Schleswig-Holstein, Germany.

Thordis Hohnstein (T)

Department of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Lutz Menzel (L)

Translational Tumor Immunology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Simge G Yüz (SG)

Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany.

Daniel Alvarez-Simon (D)

Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany.

Anne Rieke Bickenbach (AR)

Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany.

Carl Weidinger (C)

Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Nadine Mockel-Tenbrinck (N)

Miltenyi Biotec B.V. & Co.KG, Bergisch-Gladbach, Nordrhein-Westfalen, Germany.

Anja A Kühl (AA)

iPATH, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Britta Siegmund (B)

Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Jochen Maul (J)

Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Gastroenterologie am Bayerischen Platz, Berlin, Germany.

Christian Neumann (C)

Department of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany. c.neumann@charite.de.

Alexander Scheffold (A)

Institute of Immunology, Christian-Albrechts-University of Kiel & UKSH Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany. Alexander.Scheffold@uksh.de.

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