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Modulation of Dendritic Cell Behaviour Modulation of Dendritic Cell Behaviour Dissertation zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) des Fachbereiches Biologie an der Universität Konstanz vorgelegt von Markus Bruckner Konstanz, 2011 Tag der mündlichen Prüfung: 16. September 2011 Referent: PD Dr. Daniel F. Legler Referent: Prof. Dr. Marcel Leist …to my family Danksagung Diese Dissertation wurde am Biotechnologie Institut Thurgau an der Universität Konstanz (BITg), Kreuzlingen, Schweiz, unter der Leitung von Herrn PD Dr. Daniel F. Legler erstellt und betreut. Mein besonderer Dank gebührt: Meinem Doktorvater PD Dr. Daniel F. Legler für die freundschaftliche Aufnahme am BITg, die Überlassung des Themas, die unermüdliche Hilfs- und Diskussionsbereitschaft und das entgegengebrachte Interesse. Prof. Dr. Marcus Gröttrup für das entgegengebrachte Interesse, die Hilfs- und Diskussionsbereitschaft. Prof. Dr. Marcel Leist für die bereitwillige Übernahme der Zweitgutachtertätigkeit. Dr. Eva-Maria Boneberg für die technische und wissenschaftliche Unterstützung, die Diskussionen, die aufheiternden Anekdoten und für ihr stets offenes Ohr. Dr. Eva Singer und Dr. Marc Müller für die verlässliche und komplikationslose Durchführung der Blutspenden. Dr. Petra Krause und Nicola Catone für die Bereitschaft ihr Wissen und ihre Erfahrung zu teilen. Denise Dickel für ihren hochmotivierten Einsatz. Dr. Michael Basler & Dr. Margit Richter für die vielen kleinen Unterstützungen beim Erstellen dieser Arbeit. Allen Mitarbeitern des BITg und des Lehrstuhls Immunologie für das konstruktive und angenehme Arbeitsklima. Meiner Familie. List of publications Publications integrated in this thesis: Krause P*, Bruckner M*, Uermösi C, Singer E, Groettrup M, Legler DF 2009 Prostaglandin E2 enhances T cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells. Blood 113(11):2451-60 Legler DF, Bruckner M, Uetz-von Allmen E, Krause P 2010 Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. Int J Biochem Cell Biol 42(2):198-201. Review Schumann K*, Lämmermann T*, Bruckner M, Legler DF, Polleux J, Spatz JP, Schuler G, Förster R, Lutz MB, Sorokin L, Sixt M 2010 Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity 32(5):703-13 Bruckner M, Dickel D., Singer E., Legler DF 2011 Opposing forces – Prostaglandin E2 counteracts liver X receptor activation in human dendritic cells. submitted Bruckner M, Dickel D., Singer E., Legler DF 2011 Distinct modulation of chemokine expression patterns in human monocyte derived dendritic cells. submitted * contributed equally Table of contents CHAPTER I - INTRODUCTION 1 DENDRITIC CELLS IN TOLERANCE AND IMMUNITY 1 PROSTAGLANDIN E2 AT NEW GLANCE: NOVEL INSIGHTS IN FUNCTIONAL DIVERSITY OFFER THERAPEUTIC CHANCES 7 LIPIDS MODULATE DC BEHAVIOUR 14 AIM OF THE STUDY 16 CHAPTER II 17 DISTINCT MODULATION OF CHEMOKINE EXPRESSION PATTERNS IN HUMAN MONOCYTE-DERIVED DENDRITIC CELLS BY PROSTAGLANDIN E2 ABSTRACT 17 INTRODUCTION 18 RESULTS 19 DISCUSSION 24 MATERIALS AND METHODS 26 CHAPTER III 29 OPPOSING FORCES – PROSTAGLANDIN E2 COUNTERACTS LIVER X RECEPTOR ACTIVATION IN HUMAN DENDRITIC CELLS ABSTRACT 29 INTRODUCTION 30 RESULTS 31 DISCUSSION 38 MATERIALS AND METHODS 40 SUPPLEMENTS 43 CHAPTER IV 45 PROSTAGLANDIN E2 ENHANCES T-CELL PROLIFERATION BY INDUCING THE COSTIMULATORY MOLECULES OX40L, CD70 AND 4-1BBL ON DENDRITIC CELLS ABSTRACT 45 INTRODUCTION 46 RESULTS 48 DISCUSSION 56 MATERIALS AND METHODS 60 CHAPTER V 63 IMMOBILIZED CHEMOKINE FIELDS AND SOLUBLE CHEMOKINE GRADIENTS COOPERATIVELY SHAPE MIGRATION PATTERNS OF DENDRITIC CELLS ABSTRACT 64 INTRODUCTION 64 RESULTS 66 DISCUSSION 76 MATERIALS AND METHODS 78 SUPPLEMENTS 82 CHAPTER VI - GENERAL DISCUSSION 85 SUMMARY 93 ZUSAMMENFASSUNG 95 REFERENCES 97 RECORD OF CONTRIBUTIONS 117 Chapter I - Introduction Chapter I Introduction Immune responses are achieved by orchestrated events of the non-specific innate and antigen-specific adaptive immune system guided by Dendritic cells (DCs). The heterogeneous population of DCs consists of distinct functional subsets with tailored functions and tasks meeting the requirements of different immunologic scenarios in health and disease [1, 2]. As professional antigen-presenting cells (APCs), DCs sample their environment, acquire antigenic information and start communicating with the innate and adaptive immune system to orchestrate immune responses [3-5]. Thus, the understanding and modulation of DC behaviour in health and disease is of central interest in immunology and offers therapeutic chances. Dendritic Cells in tolerance and immunity DCs are the most potent APCs capable of sensing, acquiring, transferring and presenting antigenic information to cells of the adaptive immune system. Their unique ability to induce antigen-specific primary T cell responses enables them to establish an immunological memory. These features and their ability to regulate the type and magnitude of primary and secondary T cell responses highlight their crucial role in mediating immunity and tolerance [6]. Dendritic cell origins and functions Throughout the body, DCs are distributed in various tissues as precursors or fully differentiated cells in an either immature or mature state [7]. DC precursors arise from hematopoetic progenitor stem cells (HSPCs) in the bone marrow [8] in response to fms-like tyrosine kinase-3 ligand (Flt3L) [9, 10] or granulocyte-macrophage colony stimulating factor (GM-CSF) [11] and enter the bloodstream. Blood circulating immature DCs and precursors are characterized as HLA-DR+ and lineage- and almost replenish the pool of circulating blood as well as tissue resident DCs [2, 6, 12]. Alternatively, DCs can also arise from tissue- and organ-patrolling HSPCs or circulating CD14+ blood monocytes [8]. In human blood, DC subsets can be distinguished by their reciprocal surface expression of CD11c on myeloid 1 Chapter I - Introduction DCs and the Interleukin (IL)-3 receptor chain (CD123) on plasmacytoid DCs (pDCs) [13, 14]. pDCs are a specialized DC subset, primarily localized in lymphoid-tissue associated T cell zones and the blood, and are very efficient in mediating anti-viral immune responses facilitated by their ability to produce large amounts of type I interferons [15]. Moreover, they own a special antigen-processing machinery which is optimized to combat viral infections [16]. Myeloid DCs are usually termed by their tissue distribution and are classified into circulating blood DCs, lymphoid-tissue resident DCs, and migratory or non-lymphoid tissue resident DCs, such as dermal associated interstitial DCs (intDCs) or C-type lectin Langerin expressing epidermal Langerhans cells (LCs) [7, 17, 18]. Unlike pDCs, myeloid DCs are very efficient in the capture and presentation of extracellular antigens [19, 20]. Lymphoid tissue resident DCs play key roles in maintaining tolerance under steady state conditions [21] but participate in triggering specific immunity by capturing antigens in conduits of secondary lymphoid organs (SLOs) [22]. In contrast to lymphoid-tissue resident DCs, migratory, non- lymphoid tissue (peripheral) DCs play a major role in the perception and transport of peripheral acquired antigens into lymphatic tissue, thus being key in adaptive immunity and peripheral tolerance [14, 23]. Dendritic cell activation Numbers of non-activated DCs fulfil sentinel functions in tissues that are in contact with the environment, respectively portals of invading pathogens, such as skin and mucosa [8]. Non- activated DCs, herein after called immature DCs, exhibit a high endocytic activity in taking up antigens, but do not own the complete properties to efficiently prime antigen specific naive T cells, a unique feature of mature DCs [3, 24]. Using receptor-dependent or -independent endocytosis, phagocytosis or pinocytosis, immature DCs ingest apoptotic or necrotic cells, proteins, immune complexes and pathogen derived particles [4]. However, antigen uptake per se is not sufficient to convert immature DCs to professional T and B cell-educating APCs. A second stimulus, designating the subsequent outcome of the immune response, is required for activation [4]. Amongst others, pattern recognition receptors (PRRs), such as Toll like receptors (TLRs) [25, 26], cell surface C-type lectin receptors (CLRs) [27], intracytoplasmic nucleotide oligomerization domain (NOD)-like receptors (NLRs) [28] and RIG-I like receptors (RLRs) [29] provide the required stimulus upon activation with pathogen- associated molecular patterns (PAMPs) derived from microbes. Beside PAMPs, molecules harbouring danger associated molecular patterns (DAMPs), i.e. cell derived heat-shock proteins (HSPs) [30-32] or the high mobility group box protein 1 (HMGB1) [33, 34], opsonized particles captured by Fc-domain binding receptors [35, 36] as well as inflammatory cytokines [37] activate DCs. Moreover, CD40L (CD154), a member of the TNF 2 Chapter I - Introduction family expressed by a variety of cell types and originally described on activated CD4+ T helper (Th) cells [38], activates DCs via its cognate receptor CD40 expressed on DCs [39- 42]. After activation, often referred as maturation, DCs undergo a dramatic morphologic and functional transition accompanied by a switch in migratory responsiveness [43-45], shutdown of endocytic activity, up-regulation of membrane-bound co-stimulatory molecules and major histocompatibility complexes (MHCs)
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