Toll-like receptors [Elektronische Ressource] : link between innate and adaptive immunity = Toll-ähnliche Rezeptoren / vorgelegt von Sibylla Braedel-Ruoff

De
Publié le : lundi 1 janvier 2007
Lecture(s) : 35
Tags :
Source : TOBIAS-LIB.UB.UNI-TUEBINGEN.DE/VOLLTEXTE/2007/2776/PDF/DISSERTATION_BRAEDEL.PDF
Nombre de pages : 205
Voir plus Voir moins



Toll-like Receptors –
Link between Innate and Adaptive Immunity

Toll-ähnliche Rezeptoren -
Mittler zwischen angeborener und erworbener Immunität



D I S S E R T A T I O N

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

zur Erlangung des Grades eines Doktors
der Naturwissenschaften

2007

vorgelegt von
Sibylla Braedel-Ruoff TLRS – LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY









































Tag der mündlichen Prüfung: 18. Januar 2007

Dekan: Prof. Dr. L Wesemann
1. Berichterstatter: Prof. Dr. H.-G. Rammensee
2. Berichterstatter: Prof. Dr. H. Schild


TLRS – LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY


4 TABLE OF CONTENTS
Table of Contents
Abbreviations.......................................................................................................................6
Summary..............................................................................................................................9
Zusammenfassung..............................................................................................................10

Chapter 1 General Introduction ....................................................................................11

Outline of this Thesis.........................................................................................................65

Chapter 2 Legionella pneumophila Mediated Activation of Dendritic
Cells Involves CD14 and TLR2
Journal of Endotoxin Research 11 [2], 89-96(8) (2005).............................67

Chapter 3 Aspergillus fumigatus Antigens Activate Innate Immune Cells
via Toll-like Receptors 2 and 4
British Journal of Haematology 125 [3], 392-399 (2004) ..........................81

Chapter 4 The Endoplasmic Reticulum-resident Heat Shock Protein Gp96
Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway
Journal of Biological Chemistry 277 [23], 20847-20853 (2002) ...............97

Chapter 5 Glycoprotein 96-activated Dendritic Cells Induce a CD8-
biased T-Cell Response
Cell Stress Chaperones 10 [3], 221-229 (2005)........................................115

Chapter 6 Impacts of Toll-like Receptor Signaling on Priming of
Cytotoxic T-Lymphocytes in vivo
(submitted) .................................................................................................131

Chapter 7 Résumé.......................................................................................................149

References........................................................................................................................157
List of publications ..........................................................................................................196
Danksagung......................................................................................................................198
Curriculum vitae ..............................................................................................................200
Akademische Lehrer ........................................................................................................203
Lebenslauf........................................................................................................................204
5 TLRS – LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY
Abbreviations
For peptide sequences the one- or three-letter amino acid code was used. SI units and
standard abbrevations are not explained in the table.

ABTS 2,2’-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)
AIRE Autoimmune regulator
AP-1 Activator protein 1
APC Antigen presenting cell
BCR B cell receptor
Bone marrow-derived dendritic cells BMDC
Bovine serum albumin BSA
CD Cluster of differentiation
CD154 Also called CD40 ligand
CD80 Also called B7.1
Also called B7.2 CD86
Carboxyfluorescein diacetate succinimide ester CFSE
CLIP Class II-associated invariant chain peptide
CMV Cytomegalovirus
CpG DNA motif Cytosine-phosphate-guanine DNA motif
CRP C-reactive protein
CTL Cytotoxic T lymphocyte
CTLA-4 Also called CD152
DC Dendritic cell
DD Death domain
Deoxyribonucleic acid DNA
DNA-dependent protein kinase DNA-PK
DRiPs Defective ribosomal products
dsRNA Double-stranded RNA
ECSIT Evolutionarily conserved signalling intermediate in Toll pathways
Endoplasmic reticulum ER
Endoplasmic reticulum aminopeptidase associated with antigen processing ERAAP
ERK Extracellular-regulated kinase
FCS Fetal calf serum
FITC Fluorescein isothiocyanate
GM-CSF Granulocyte-macrophage colony-stimulating facto
Gp96 96-kDa glycose-regulated protein
HAU Haemagglutinating units
HCV Hepatitis C virus
Hib Haemophilus influenzae type b
Human immunodeficiency virus HIV
Human leukocyte antigen HLA
Hsp Heat-shock protein
HSV-1 Herpes simplex virus 1
Ig Immunoglobulins
Invariant chain protein Ii protein
IKKs IkB kinases
IL Interleucin
6 ABBREVIATIONS
Interferon INF
IRAK4, IRAK1 IL-1R-associated kinase 4, IL-1R-associated kinase 1
ISRE Interferon-stimulated response elements
ITAM Immunoreceptor tyrosine-based activation motif
IB Inhibitor of NF-B
JUN N-terminal kinase JNK
kDa Kilo Dalton
LBP Lipopolysaccharide binding protein
LCMV Lymphocytic choriomeningitis virus
LDL Low density lipoprotein
Lipopolysaccharide, also called endotoxin LPS
LRR motif Leucin-rich repeat motif
LTA Lipoteichonic acid
MAL MyD88-adaptor-like protein
MALP-2 Macrophage-activating lipopeptide-2 kDa
Mucosa-associated lymphoid type MALT
MAP Mitogen-associated protein
MARCO Macrophage receptor with collagenous structure
MBL Mannan-binding lectin
MCMV Murine cytomegalovirus
Major histocompatibility complex MHC
MIIC MHC class II compartments
MLA Monophosphoryl lipid A
MM-LDL Minimally modified-LDL
MSR Macrophage scavenger receptors
Mycobacterium tuberculosis MTB
MyD88 myeloid differentiation factor 88, myeloid differentiation primary-response protein 88
NF- kB Nuclear factor-kB
NOD Nucleotide-binding oligomerization domain
ODN Oligodeoxynucleotide
Proteasome-activator PA28
Pam Cys (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-cysteine 3
PAMP Pathogen associated molecular pattern
PE Phycoerythrin
pH Potentia Hydrogenii
Phosphatidylinositol 3-kinase PI3K
PKR IFN-inducible dsRNA-dependent protein kinase
Poly(I:C) Polyinosine-polycytidylic acid (dsRNA analogue)
PPR Pattern recognition receptor
RNA Ribonucleic acid
CD180, radioprotecitve 105 RP105
RSV Respiratory syncytial virus
SAP Serum amyloid protein
SAPK Stress-activated protein kinases
SAP-kinase Stress-associated protein kinase
Single immunoglobulin IL-1R-related molecule SIGIRR
SLE Systemic lupus erythematosus
SOCS Suppressor of cytokine signalling
ssRNA Single-stranded RNA
TAK1-binding proteins TAB1/TAB2/TAB3
7 TLRS – LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY
TAK1 Transforming growth factor-b(TGF-b)-activated kinase
TAP Transporter associated with antigen processing
TAPA-1 Also called CD81
TCR T cell receptor
T T helper cell H
TIR-domain-containing molecule 1, also known as TRIF TICAM1
TICAM2 TIR-domain-containing molecule 2, also known as TRAM
TIR domain Toll/IL-1 receptor domain
TIRAP TIR domain containing adaptor protein, also known as MAL
TLR Toll-like receptor
Tumor necrosis factor TNF
TOLLIP Toll-interacting protein
TRAF Tumor-necrosis factor (TNF)-receptor-associated factor
TRAM TRIF-related adaptor molecule, also known as TICAM2
TRIF TIR domain-containing adapter inducing IFN-b, also known as TICAM1
Vaccinia virus VV

Figures are numbered for each chapter separately. If not otherwise stated, the
mentioned figure numbers refer to the figures in the same chapter.
8 SUMMARY - ZUSAMMENFASSUNG
Summary
Toll-like receptors (TLR) function as pattern recognition receptors (PRR) and
recognize highly conserved pathogen-associated molecular patterns. They not only
activate an immediate innate immune defense but are additionally able to induce an
adaptive immune response. The questions, which substances are recognized via TLRs,
which specific TLRs are involved by a given danger signal and which mechanisms
finally lead to the activation of the adaptive immune system, were the focus of this
thesis.
Investigation of the bacteria Legionella pneumophila, the causative agent of
Legionnaires’ disease, revealed that lipopolysaccharide (LPS) purified from the cell
wall as well as the whole bacteria activate antigen-presenting cells (APC) via TLR2-
dependent signal transduction. Thus, LPS was identified as the main structure for the
recognition of L. pneumophila by the innate immune system (Chapter 2).
Furthermore, TLRs play a central role in the activation of the innate immune system
by antigens of the fungus A. fumigatus, which causes invasive aspergillosis. Thereby,
the involvement of TLR2 and TLR4 results in the release of different pro-
inflammatory cytokines by APCs (Chapter 3). TLRs, however, do not only recognize
exogenous pathogen-derived molecules, but also endogenous alarm structures. This
could be demonstrated for the ER-resident heat shock protein Gp96, which, as carrier
of tumor-specific peptides, is able to elicit protective immunity against tumors. The
Gp96-induced activation of dendritic cells via TLR4 and TLR2 (Chapter 4) finally
leads to the expansion of antigen-specific CD8-positive T cells in vivo and in vitro
(Chapter 5). The relevance of TLR-mediated activation of the immune system for the
induction of adaptive immune responses could also be demonstrated in a more general
system: “priming” of cytotoxic T cells (CLTs) during a virus infection requires either
+CD4 T helper cells or TLR-mediated signals. In the absence of both, CTL priming is
impaired. In a system of weaker immunogenic antigens, TLR signals are even strictly
required (Chapter 6).
Toll-like receptors are more than recognition receptors of the innate immune system –
they link innate and adaptive immunity.

9 TLRS – LINK BETWEEN INNATE AND ADAPTIVE IMMUNITY
Zusammenfassung
Toll-ähnliche Rezeptoren (TLR) erkennen als Pattern-Recognition- Rezeptoren (PRR)
stark konservierte Pathogen-assoziierte molekulare Strukturen. Sie aktivieren nicht nur
eine sofort einsetzende angeborene Immunabwehr, sondern sind zudem in der Lage,
eine adaptive Immunantwort auszulösen. Die Fragen, welche Substanzen als
Gefahrensignale über TLRs erkannt werden, welche speziellen TLRs diese Aufgabe
für individuelle Gefahrenmoleküle übernehmen und welche Mechanismen schließlich
zur Aktivierung des erworbenen Immunsystems führen, standen im Mittelpunkt dieser
Arbeit.
Untersuchungen des Bakteriums Legionella pneumophila, des Erregers der
Legionärskrankheit, zeigten, dass sowohl das Bakterium als Ganzes als auch aus der
Zellwand isoliertes Lipopolysaccharid (LPS) Antigen-präsentierende Zellen (APC)
über TLR2 aktivieren. LPS wurde somit als Hauptstruktur zur Erkennung von L.
pneumophila durch das angeborene Immunsystem identifiziert. (Kapitel 2). Auch
Antigene des Pilzes Aspergillus fumigatus, der die invasive Aspergillose hervorruft,
wurden als TLR-vermittelte Gefahrensignale identifiziert. Dabei führt die Involvierung
von TLR2 und TLR4 zur Freisetzung unterschiedlicher pro-inflammatorischer
Zytokine durch APCs (Kapitel 3). TLRs erkennen aber auch endogene
Gefahrenstrukturen. Dies konnte für das ER-ständige Hitzeschockprotein Gp96, das
als Trägermolekül von tumorspezifischen Peptiden eine protektive Immunität gegen
Tumoren hervorruft, gezeigt werden. Die Gp96-induzierte Aktivierung dendritischer
Zellen über TLR4 und TLR2 (Kapitel 4) mündet schließlich in eine Expansion von
+antigen-spezifischen CD8 T Zellen (Kapitel 5). Die Bedeutung der TLR-vermittelten
Aktivierung des Immunsystems für die Entwicklung einer adaptive Immunantwort
konnte auch in einem verallgemeinerten Modell verdeutlicht werden: Für das
+„Priming“ cytotoxischer T-Zellen während einer Virusinfektion sind entweder CD4
T-Helferzellen oder aber TLR-vermittelte Signalwege nötig. Sind beide Signalwege
blockiert, findet kein Priming statt. In einem System mit schwächer immunogenen
Antigenen sind TLR-Signale sogar absolut notwendig (Kapitel 6).
TLRs sind mehr als nur Erkennungsrezeptoren des angeborenen Immunsystems – sie
verknüpfen angeborene und erworbene Immunität.
10

Soyez le premier à déposer un commentaire !

17/1000 caractères maximum.

Diffusez cette publication

Vous aimerez aussi