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Table of contents
ABSTRACT
RÉSUMÉ
TABLE OF CONTENTS
LIST OF FIGURES
LIST OF TABLES
REMERCIEMENTS
ABBREVIATIONS
FOREWORD
RESEARCH PLAN
I.! DEVELOP TOOLS FOR SCREENING RARE ANTIGEN-SPECIFIC RESPONSES IN HUMANS
II.! EVALUATE THE IMPACT OF CHRONIC INFECTION ON THE PREIMMUNE REPERTOIRE ….
III.! STUDY THE IMPACT OF CXCR3 RECEPTOR ON INEXPERIENCED T CELLS
CHAPTER 1. GENERAL INTRODUCTION
I.! PREIMMUNE REPERTOIRE
A.! THYMIC DEVELOPMENT
1)! Thymus anatomy and function
2)! Early thymocyte development
3)! Thymic selection of the MHC-restricted preimmune repertoire
4)! Maturation and emigration of mature SP thymocytes
B.! PERIPHERAL NAIVE T CELLS
1)! Recent Thymic Emigrants
2)! Population size and TCR repertoire
3)! Homeostasis and homeostatic proliferation
4)! CD5 expression and dynamic tuning of lymphocytes
5)! Activation, differentiation and activation-induced cell death
6)! Phenotypic and functional diversity
7)! Impact of precursor frequency and diversity
II.! CHRONIC INFLAMMATION
1)! General introduction
2)! HCV as a model of chronic inflammation
(a)! Epidemiology
(b)! Virus genome
(c)! Tropism and entry receptors
(d)! From acute to chronic infection
(e)! Extrahepatic manifestations
(f)! Treatment and clearance benefits
(g)! Antiviral immune responses
3)! HBV as a comparative model of chronic hepatitis
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4)! Viro-induced chronic inflammation
5)! T cells and inflammation
III.! T CELL TRAFFICKING
1)! Short introduction about chemokines
2)! Naive T cell trafficking
3)! Effector and resident memory T cells trafficking
4)! Role of CXCR3 in T cell biology
5)! Focus on CXCL10
CHAPTER 2. DEVELOP TOOLS FOR SCREENING RARE ANTIGEN-SPECIFIC RESPONSES
I.! INTRODUCTION
II.! TETRAMER ASSOCIATED MAGNETIC ENRICHMENT (TAME)
A.! PREPARATION OF PMHCI TETRAMERS
B.! PREPARATION OF PHOTOCLEAVABLE PMHCI TETRAMERS
C.! DEVELOPMENT OF TAME FOR HUMAN SAMPLES
D.! TAME INCREASES DETECTION OF AG-SPECIFIC T CELLS BY UP TO 100-FOLD
E.! DETECTION OF NAIVE CD8
T CELLS SPECIFIC FOR HIV GAG P1777-85
F.! ENRICHMENT AND ENUMERATION OF MULTIPLE SPECIFICITIES
III.! DISCUSSION
A.! TAME PERMITS ENUMERATION AND CHARACTERIZATION OF RARE AG-SPECIFIC T CELLS FROM HUMAN PERIPHERAL BLOOD
B.! EPITOPES HAVE CONSERVED PRECURSOR FREQUENCIES AMONG INDIVIDUALS.
IV.! PROSPECTIVES
CHAPTER 3. DEFINE THE INFLUENCE OF CHRONIC HCV INFECTION ON THE PREIMMUNE REPERTOIRE.
I.! INTRODUCTION
II.! EVALUATION OF THE PREIMMUNE REPERTOIRE DURING CHRONIC HCV
A.! GATING STRATEGY
B.! BULK LEVEL
C.! ANTIGEN-SPECIFIC LEVEL
D.! NAIVE T CELL HOMEOSTASIS DURING CHRONIC HCV
III.! DISCUSSION
IV.! PROSPECTIVES
CHAPTER 4. STUDY THE IMPACT OF CXCR3 RECEPTOR ON INEXPERIENCED T CELLS
I.! INTRODUCTION
I.! IN THE THYMUS
II.! IN PERIPHERY
A.! MP CELLS IN THE BLOOD OF NON-IMMUNIZED CXCR3-/- ANIMALS
B.! DISTINCT TCR ACTIVATION PATTERN
C.! MP OTI CELLS IN THE SKIN OF UNIMMUNIZED WT ANIMALS
D.! MP OTI CELLS ARISE IN HOMEOSTATIC ENVIRONMENTS
III.! DISCUSSION
IV.! PROSPECTIVES
CHAPTER 5. GENERAL DISCUSSION
I.! IMMUNOPHENOTYPING CHALLENGES
II.! PREIMMUNE REPERTOIRE AND PERSONALIZED MEDICINE
III.! PREIMMUNE REPERTOIRE AND PERSISTENT VIRUSES
METHODS
I.! GENERATION OF PMHC CLASS I TETRAMERS THROUGH LIGAND EXCHANGE.
II.! TAME PROTOCOL
MANUSCRIPTS
REFERENCES
