Zelluläre Quellen und funktionelle Signifikanz von IL-6 bei der Entstehung autoreaktiver T Zell-Antworten im peripheren Immunkompartiment und im zentralen Nervensystem
Final Report Abstract
In this joint project, we managed to generate major tools to address the question of relevant cellular sources of IL-6 during autoimmune inflammatory diseases in vivo. These tools include T cell conditional IL-6Ra KO mice, B cell conditional IL-6 KO mice, DC conditional IL-6 KO mice, and finally a completely novel reporter mouse strain that has the potential to indicate cellular sources of IL-6 in vivo by expression of the cell surface marker Thy1.1 and concomitantly a cytosolic fluorescent protein (Cerulean) in those cells that actively transcribe the Il6 locus. Here, we first chose a BAC transgenic approach that was unsuccessful since the reporter construct was silenced after genomic integration. However, after re-thinking our strategy and switching to a targeted knock-in approach, we succeeded in generating this IL-6 reporter mouse strain and are currently characterizing it in various disease models. Using this package of novel experimental strategies, we have already made substantial findings including the fact that dendritic cells are the most relevant source of IL-6 in MOG peptide induced EAE while B cell derived IL-6 is dispensable for the priming of pathogenic T cells irrespective of whether EAE is induced with MOG35-55 peptide or MOG protein. In addition, our tools will provide us with the unique opportunity for further characterization of the sources of IL-6 that are relevant for adaptive humoral and cellular immune responses (in settings of autoimmunity, chronic inflammation, and infection). Thus, we will be able to generate experimental platforms for improving therapeutic strategies in autoimmune diseases and efficient vaccination strategies in viral infections. While some initial milestones of this project have already been published, the major breakthroughs that we have achieved in the last 6 to 9 months are currently worked up in follow-up experiments which will be finalized and hopefully published in the near future.
Publications
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(2011) Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. Journal of Immunology, 187: 6346-6356
Loschko J, Heink S, Hackl D, Dudziak D, Reindl W, Korn T & Krug AB
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(2011) Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE. Journal of Experimental Medicine, 208: 2465-2476
Rothhammer V, Heink S, Petermann F, Srivastava R, Claussen MC, Hemmer B & Korn T
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(2012) Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor+ regulatory T cells. Immunity, 37: 1-12
Yogev N, Frommer F, Lukas D, Kautz-Neu K, Karram K, Ielo D, von Stebut E, Probst H-C, van den Broek M, Riethmacher D, Birnberg T, Blank T, Reizis B, Korn T, Wiendl H, Jung S, Prinz M, Kurschus FC & Waisman A
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(2012) The potassium channel KIR4.1 as an immune target in multiple sclerosis. The New England Journal of Medicine, 367: 115-123
Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T & Hemmer B
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(2014) α4-integrins control viral meningoencephalitis through differential recruitment of T helper cell subsets. Acta Neuropathologica Communications, 2: 27-43
Rothhammer V, Muschaweckh A, Gasteiger G, Petermann F, Heink S, Busch D, Heikenwälder M, Hemmer B, Drexler I & Korn T
