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CD40 thesis IntroChapters

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CHAPTER 1

BIOLOGICAL OUTCOMES OF THE CD40−CD40L INTERACTION

1.1 Discovery of CD40 (also named CDw40 and Bp50) 4
1.1.1 Identification of CD40 4
1.1.2 Cellular expression of CD40 4
1.2 Discovery of CD40−ligand (also named CD40L, CD154, gp39 and T-BAM) 6
1.2.1 Cloning of CD40L 6
1.2.2 Cellular expression of CD40L 7
1.3 Other proteins interact with CD40 9
1.4 CD40L binds to other receptors 9
1.5 Level of CD40 crosslinking is important for activation of biological responses 10
1.5.1 Engagement of CD40 with anti-CD40 Ab 10
1.5.2 Engagement of CD40 with CD40L 11
1.6 CD40 plays a central role in immune response 12
1.6.1 Discovery of the X−linked hyper IgM syndrome 12
1.6.2 Role of CD40 in B lymphocytes 12
1.6.2.1 Effect of anti-CD40 mAb on B cell proliferation 13
1.6.2.2 CD40 engagement and B cell activation 13
1.6.2.3 CD40 is important for isotype switching 14
1.6.2.4 CD40 is important for rescue from apoptosis of mature B lymphocytes 16
1.6.3 Role of CD40 in other immune cells 16
1.7 Function of CD40 in malignant cells 17


CHAPTER 2

CD40 AND CD40L: GENES AND PROTEINS

2.1 Characteristics of the CD40 protein sequence 19
2.1.1 The human sequence 19
2.1.2 The mouse sequence 20
2.2 Regulation of CD40 expression 21
2.2.1 Organization of the CD40 gene 21
2.2.1.1 The mouse gene 21
2.2.1.2 The human gene 21
2.2.2 Transcriptional regulation of CD40 expression 22
2.2.3 Post-transcriptional regulation of CD40 expression 23
2.2.3.1 Alternative splicing of the CD40 mRNA 23
2.2.3.2 Stability of the CD40 mRNA 24
2.2.4 Post-translational regulation of CD40 expression 25
2.3 Characteristics of the CD40L protein sequence 26
2.3.1 The mouse sequence 26
2.3.2 The human sequence 27
2.4 Regulation of CD40L expression 28
2.4.1 Organization of the CD40L gene 28
2.4.2 Transcriptional regulation of CD40L expression 28
2.4.3 Post-transcriptional regulation of CD40L expression 30
2.4.4 Post-translational regulation of CD40L expression 30
2.5 Three-dimensional view of the CD40−CD40L interaction 32
2.5.1 The TNF/TNF-R superfamily 32
2.5.2 The TNF family proteins 36
2.5.3 The TNF-R family proteins 37
2.5.4 The three-dimensional structure of CD40L 39
2.5.5 Three-dimensional model of the CD40–CD40L interaction 40
2.5.5.1 A three-dimensional model for CD40 40
2.5.5.2 Residues important for the CD40–CD40L interaction 41
2.5.5.3 Construction of a CD40–CD40L interaction model 42
2.5.6 Usefulness of the three-dimensional model of the CD40–CD40L interaction 45


CHAPTER 3

CELL SIGNALING INITIATED FROM CD40

3.1 CD40 clustering and downstream signaling 46
3.1.1 Consequences of membrane receptor crosslinking in cell signaling 46
3.1.2 Minimal CD40 oligomerization requirement for activation of cell signaling 46
3.1.2.1 Extracellular oligomerization 46
3.1.2.2 Intracellular oligomerization 47
3.1.3 Structural mechanisms governing initiation of intracellular signals 48
3.2 Role of pre-ligand binding assembly domain in CD40 49
3.2.1 The PLAD domain 49
3.2.2 PLAD requirement for CD40 signaling 50
3.3 CD40 signaling is initiated within membrane rafts 51
3.3.1 Membrane rafts 51
3.3.2 CD40 is localized into lipid raft microdomains 52
3.3.3 Caveolae are implicated in CD40 signaling 52
3.3.4 Translocation of CD40 into lipid rafts 53
3.4 CD40−induced cell signaling 54
3.4.1 CD40–activated signaling pathways 54
3.4.1.1 Intermediates implicated in CD40 signaling 54
3.4.1.2 Common signaling pathways activated by CD40 55
3.4.2 Implication of TRAF adaptor molecules 56
3.4.2.1 CD40 signals through adaptor molecules 56
3.4.2.2 The TNF-R–associated factors 56
3.4.2.2.1 The TRAF family 56
3.4.2.2.2 TRAFs are located into lipid rafts 57
3.4.2.2.3 Regulation of TRAF functions 57
3.4.2.2.4 TRAF protein structure 58
3.4.2.3 The TRAF–CD40 interaction 59
3.4.2.3.1 TRAF–binding sites 59
3.4.2.3.2 CD40–mediated activation of TRAFs 60
3.4.2.3.3 The TRAF–CD40 interaction viewed at the three-dimensional level 61
3.4.2.4 TRAF–specific signaling 62
3.4.2.4.1 TRAF1 62
3.4.2.4.2 TRAF2 63
3.4.2.4.3 TRAF3 63
3.4.2.4.4 TRAF4 64
3.4.2.4.5 TRAF5 65
3.4.2.4.6 TRAF6 65
3.4.3 TRAF–independent CD40 signaling 66

!Poster 1: summary of the signaling pathways engaged by CD40 67


CHAPTER 4

THE CD40−CD40L INTERACTION AS A TARGET FOR IMMUNOTHERAPY

4.1 Blockade of the CD40–CD40L interaction 70
4.1.1 CD40-based treatment of autoimmune diseases 71
4.1.1.1 Systemic Lupus Erythematosus 72
4.1.1.2 An anti-CD40L therapy for other autoimmune diseases? 74
4.1.2 Chronic inflammation 75
4.1.3 Transplantation 76
4.2 Boosting the immune response by activation of the CD40 signaling 77
4.2.1 Hyper-IgM syndrome and immunodeficiencies 77
4.2.2 Infections 78
4.2.3 Vaccination 80
4.2.4 Cancer 82
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