AICL is a ligand for the human NK receptor NKp80/KLRF1 and mediates an activating crosstalk between NK cells and monocytes [Elektronische Ressource] = AICL ist ein Ligand des humanen NK-Rezeptors NKp80/KLRF1 und vermittelt eine aktivierende Interaktion zwischen NK-Zellen und Monozyten / vorgelegt von Stefan Welte

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Sujets

• Gesundheit

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2007
• Nombre de lectures: 4
• Langue: English
• Poids de l'ouvrage: 6 Mo

Extrait

AICL is a ligand for the human NK receptor
NKp80/KLRF1 and mediates an activating crosstalk
between NK cells and monocytes


AICL ist ein Ligand des humanen NK Rezeptors
NKp80/KLRF1 und vermittelt eine aktivierende
Interaktion zwischen NK-Zellen und Monozyten



DISSERTATION

der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften




2007

vorgelegt von

Stefan Welte


III




























Tag der mündlichen Prüfung: 29. März 2007

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. H.-G. Rammensee
2. Berichterstatter: PD Dr. A. Steinle
3. Berichterstatter Prof. H.-M. Jäck
IV V

Preface

All four chapters in the results and discussion section of this thesis have been published
before. At the beginning of each chapter, it is indicated which experiments were done by
the author of this thesis, which persons contributed to the publication, and in which
journal the work has been published.






VI


Table of Contents 1
1 Introduction......................................................................... 3
1.1 Principles of the innate immune system..................................... 3
1.1.1 Immunobiology of NK cells................................................................ 4
1.1.1.1 NK cell recognition and the “missing-self hypothesis” ................ 4
1.1.1.2 Inhibitory receptors ..................................................................... 5
1.1.1.3 Activating NK receptors .............................................................. 7
1.1.1.4 Viral modulation of NK cell immunity ......................................... 8
1.1.1.5 NK licensing................................................................................9
dim bright
1.1.1.6 The CD56 and CD56 NK subsets in humans................... 11
1.1.1.7 Unconventional T cells subsets: T cells and NKT cells........... 11
1.1.2 Monocytes and macrophages........................................................... 13
1.1.2.1 Hematopoietic differentiation of myeloid cells ........................... 13
1.1.2.2 Monocyte heterogeneity ............................................................ 15
1.1.2.3 Specialized tissue macrophages................................................. 17
1.1.3 Dendritic cells .................................................................................. 18
1.1.3.1 Mouse and human dendritic cell subsets.................................... 19
1.1.3.2 Antigen capture and maturation of DCs..................................... 21
1.1.3.3 The final outcome of antigen-presentation by DCs:
induction of immunity or tolerance............................................ 22
1.1.3.4 C-type lectin receptors on dendritic cells 23
1.1.4 Pattern recognition in the innate immune system........................... 27
1.1.4.1 Pathogen-associated molecular patterns (PAMPs) and
pattern-recognition receptors (PRRs) ....................................... 27
1.1.4.2 Toll-like receptors...................................................................... 28
1.1.5 Cytokines as regulators of innate and adaptive immunity ............... 30
1.1.6 NK cell/DC crosstalk........................................................................ 32
1.1.6.1 DC interaction with innate lymphocytes .................................... 33
1.1.6.2 DC/NK interactions in peripheral and in secondary
lymphoid tissues 35
1.1.6.3 Reciprocal activating cross-talk between NK cells and DCs....... 35
1.1.6.4 Cross-talk during viral infection ................................................ 38
1.1.7 Genes encoded in the natural killer gene complex (NKC)............... 38
1.1.7.1 Structural aspects of C-type lectin-like molecules ...................... 38
1.1.7.2 Overall organization and evolution of the NKC.......................... 41
1.1.7.3 Important NKC-encoded receptors and their ligands................. 43
1.1.7.4 The activating NK receptor NKp80/KLRF1 .............................. 46
1.2 Aims of the thesis ......................................................................47
1.3 References................................................................................. 48
2 Results and Discussion ...................................................... 65
2.1 The biology of NKG2D and its ligands......................................65
2.1.1 Selective intracellular retention of virally induced NKG2D
ligands by the human cytomegalovirus UL16 glycoprotein............. 65
2.1.1.1 Abstract.....................................................................................65
2.1.1.2 Introduction .............................................................................. 66 2 Table of Contents
2.1.1.3 Materials and Methods...............................................................67
2.1.1.4 Results .......................................................................................72
2.1.1.5 Discussion .................................................................................81
2.1.1.6 Acknowledgements....................................................................83
2.1.1.7 References83
+
2.1.2 NKG2D dysfunction impairs NK and CD8 T cell responses in
vivo .................................................................................................87
2.1.2.1 Abstract.....................................................................................87
2.1.2.2 Introduction...............................................................................87
2.1.2.3 Materials and Methods...............................................................89
2.1.2.4 Results94
2.1.2.5 Discussion105
2.1.2.6 Acknowledgements..................................................................109
2.1.2.7 References109
2.2 Modulation of the innate immune system.............................. 115
2.2.1 A CD14 domain with lipopolysaccharide-binding and -
neutralizing activity........................................................................115
2.2.1.1 Abstract...................................................................................115
2.2.1.2 Introduction.............................................................................115
2.2.1.3 Materials and Methods.............................................................118
2.2.1.4 Results .....................................................................................122
2.2.1.5 Discussion ...............................................................................131
2.2.1.6 Acknowledgements..................................................................135
2.2.1.7 References135
2.2.2 Mutual activation of natural killer cells and monocytes
mediated by interaction between the human NK receptor
NKp80 and the myeloid-specific receptor AICL ............................143
2.2.2.1 Abstract...................................................................................143
2.2.2.2 Introduction.............................................................................143
2.2.2.3 Materials and Methods.............................................................145
2.2.2.4 Results .....................................................................................149
2.2.2.5 Discussion ...............................................................................167
2.2.2.6 Acknowledgements..................................................................170
2.2.2.7 References171
3 Summary ..........................................................................176
Zusammenfassung.................................................................177
4 Abbreviations ...................................................................178
5 Acknowledgements ..........................................................180
6 Publications......................................................................183
7 Scholarships .....................................................................184
8 Academic Teachers ..........................................................185
9 Curriculum Vitae..............................................................186 3Introduction
1 Introduction
1.1 Principles of the innate immune system
Pathogens infect the human body through a variety of routes. They can enter via the
mucosal surfaces or the external epithelial surfaces during physical contact or in the
case of wounds, punctures or bites. If a pathogen has successfully overcome these
protective surfaces the human body launches a rapid innate response in order to
prevent pathogen proliferation until the primary adaptive response consisting of T
and B cells provides antigen-specific protection after 4 to 7 days. These innate
mechanisms can act very fast within minutes or a few hours because there is no
requirement for clonal expansion. In most ca