Proteolytic shedding of NKG2D ligands from tumour cells [Elektronische Ressource] = Proteolytische Freisetzung von NKG2D-Liganden durch Tumorzellen / vorgelegt von Inja Waldhauer

Iw

Sujets

• Biologie

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2008
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Proteolytic shedding of NKG2D ligands
from tumour cells

Proteolytische Freisetzung von NKG2D
Liganden durch Tumorzellen



DISSERTATION



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

zur Erlangung des Grades eines Doktors
der Naturwissenschaften




2008

vorgelegt von

Inja Waldhauer
III




































Tag der mündlichen Prüfung: 19.02.08

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

All four chapters in the “results and discussion” section of this thesis have been
published before or have been submitted for publication. At the beginning of each
chapter, it is indicated which experiments were done by the author of this thesis and
who else contributed to the presented work. VI
Table of contents 1
1 Introduction........................................................................... 3
1.1 The immune system...................................................................... 3
1.1.1 The history of NK cells..............................................................4
1.1.2 NK cell characteristics ...............................................................6
1.1.3 NK cell receptors .......................................................................7
1.1.3.1 Inhibitory receptors.................................................................7
1.1.3.2 Activating receptors................................................................8
1.1.4 The activating NK receptor NKG2D.........................................9
1.1.5 NKG2D ligands11
1.1.6 NKG2D ligand expression.......................................................14
1.1.7 Implications of NK cells for cancer immunosurveillance .......15
1.1.8 Tumour immune evasion .........................................................17
1.2 Metalloproteases......................................................................... 20
1.2.1 “A Disintegrin and Metalloprotease” (ADAM) proteins.........20
1.2.1.1 Structure and properties of ADAMs.....................................20
1.2.1.2 Regulation of ADAMs26
1.2.1.3 ADAMs and diseases............................................................27
1.2.1.4 TACE....................................................................................31
1.2.1.5 ADAM10..............................................................................32
1.3 Aim of the thesis.......................................................................... 33
1.4 References ................................................................................... 34
2 Results and discussion......................................................... 54
2.1 Proteolytic Release of Soluble UL16-Binding Protein 2
from Tumour Cells..................................................................... 54
2.1.1 Abstract ....................................................................................54
2.1.2 Introduction..............................................................................55
2.1.3 Materials and Methods.............................................................56
2.1.4 Results......................................................................................58
2.1.5 Discussion................................................................................64
2.1.6 Acknowledgement ...................................................................66
2.1.7 References66
2.2 TGF- β and metalloproteinases differentially suppress
NKG2D ligand surface expression on malignant glioma
cells ..........................................................................................69
2.2.1 Abstract ....................................................................................69
2.2.2 Introduction..............................................................................70
2.2.3 Materials and methods .............................................................71
2.2.4 Results......................................................................................74
2.2.5 Discussion................................................................................81
2.2.6 Acknowledgement ...................................................................84 2 Table of contents
2.2.7 References ............................................................................... 84
2.3 Tumour-associated MICA is shed by ADAM proteases.........89
2.3.1 Abstract.................................................................................... 89
2.3.2 Introduction ............................................................................. 90
2.3.3 Materials and Methods ............................................................ 91
2.3.4 Results ..................................................................................... 94
2.3.5 Discussion.............................................................................. 101
2.3.6 Acknowledgements ............................................................... 103
2.3.7 References 103
2.4 Mutual activation of natural killer cells and monocytes
mediated by interaction between the human NK receptor
NKp80 and the myeloid-specific receptor AICL ...................107
2.4.1 Abstract.................................................................................. 107
2.4.2 Introduction ........................................................................... 107
2.4.3 Materials and Methods .......................................................... 109
2.4.4 Results ................................................................................... 113
2.4.5 Discussion.............................................................................. 132
2.4.6 Acknowledgements ............................................................... 135
2.4.7 References ............................................................................. 136
3 Summary............................................................................ 140
4 Abbreviations..................................................................... 142
5 Acknowledgement ............................................................. 145
6 Publications........................................................................ 146
7 Academic teachers 147
8 Curriculum Vitae .............................................................. 148
Introduction 3
1 Introduction

1.1 The immune system

The immune system is a complex network of specialised cells and organs. The main
function of the immune system is to protect the organism from invading pathogens but
also from altered cells such as tumour cells. In most cases our immune system is able to
control infections. This control is based on the ability of the immune system to
distinguish between self, altered-self and foreign. Non-self substances invading the
body can trigger the immune system. These substances which can be, for example parts
of foreign cells, bacteria or viruses are called antigens (antibody generating). These
antigens contain epitopes recognised by the immune system. Antigenic peptides are
presented to the immune system by a specific set of self markers, the major
histocompatibility complex (MHC) molecules which are expressed by nearly all normal
body cells. The phenomenon that the immune system does not react against “self”
structures is called immunological tolerance. Defects in this tolerance result in
autoimmunity. The immune system is also able to recognise alterations on the surface of
malignant “self” cells. This phenomenon is called tumour immunosurveillance.
The immune system is composed of two major parts, the adaptive and the innate
immune system. The innate immune system is our first line of defence against
pathogens and infectious agents. The elements of the innate immune system include
anatomical barriers, soluble molecules and cellular components. Cellular components of
the innate immune system are granulocytes, macrophages, monocytes, mast cells and
natural killer (NK) cells. These cells are able to eliminate invading pathogens without
prior sensitization or activation. Characteristics of the innate immunity are that the
defence mechanisms are for the most part constitutively present and ready to be
mobilised upon infection. In addition, it is not antigen specific, but recognises a variety
of organisms due to certain surface molecules. Recent studies have shown that NK cells
participate also in cancer immunosurveillance. In the following chapter NK cell biology
is described in detail. The adaptive immune system is the second line of defe