How the Immune System Recognizes Self and Nonself	2
	Daisuke Kitamura	3
	Immunoreceptors and Their Signaling	3
	Preface	5
	Contents	7
	List of Authors	10
	Color Plates	13
	1 Recognition of Pathogens: Toll-Like Receptors	17
	1.1 Introduction	17
	1.2 Innate Immunity	17
	1.2.1 Immune Responses in Drosophila	18
	1.2.2 Discovery of TLR in Mammals	19
	1.3 Pathogen Recognition by TLR	21
	1.4 Toll-Like Receptor Signaling Pathways	25
	1.4.1 Proinflammatory Cytokine Pathways	26
	1.4.2 TRIF-Dependent Pathway	28
	1.4.3 TLR7- and TLR9-Mediated Type I IFN Production	31
	1.4.4 Other Molecules Involved in TLR Signaling	31
	1.5 Negative Regulation of TLR Signaling	33
	1.6 Conclusion and Future Prospects	38
	References	39
	2 Strategies of Natural Killer (NK) Cell Recognition and Their Roles in Tumor Immunosurveillance	53
	2.1 Introduction: An Interesting Epistemological Case	53
	2.2 Natural Killer Cells in Innate Immunity	54
	2.3 Natural Killer Cell Recognition of “Missing-Self”: An Array of Inhibitory Cell Surface Receptors	56
	2.4 Complexity of the “NK Cell Zipper”	60
	2.4.1 Natural Cytotoxicity Receptors	61
	2.4.2 NKG2D	62
	2.4.3 CD16	63
	2.4.4 Activating Homologues of Inhibitory MHC Class I Receptors	64
	2.4.5 Natural Killer Cell Co-stimulatory and Adhesion Molecules	65
	2.5 Coordination of NK Cell Activating and Inhibitory Signals in Cancer	69
	2.6 Programming a “Natural” Killer: Steady-State and Situation- Speci . c Regulation of NK Effector Functions	78
	2.6.1 Natural Killer Responsiveness to MHC Class I and Missing- Self	79
	2.6.2 Natural Killer Responsiveness to Activating NK Ligands	82
	2.7 Conclusions and Perspectives: NK Cells, “Self Versus Nonself,” and Cancer	83
	References	83
	3 Recent Progress on Paired Immunoglobulin- Like Receptors	98
	3.1 Introduction	98
	3.2 PIR Expression by Early Hematopoietic Cells	100
	3.3 PIR Expression by Thymocyte Progenitors	101
	3.4 Differentiation Potential of PIR+ and PIRLymphoid Progenitors	102
	3.5 PIR Expression by Dendritic Cell Precursors	104
	3.6 PIR Ligands	105
	3.7 Paired Immunoglobulin-Like Receptor Function	107
	3.8 Conclusion	109
	References	110
	4 Self–nonself Recognition through B-Cell Antigen Receptor	114
	4.1 Introduction	114
	4.2 Signal Transduction from BCR	116
	4.3 BCR Signaling Pathways for Immune Response	127
	4.4 BCR Signaling Pathways for Self Tolerance 4.4.1 Clonal Deletion	131
	4.5 Concluding Remarks: To Respond or Not to Respond, That is the Question	135
	References	137
	5 How Do T Cells Discriminate Self from Nonself?	148
	5.1 Introduction	148
	5.2 Structure of the TCR Complex	150
	5.3 How Does the	155
	5.4 TCR Assembly During Intrathymic Development	162
	5.5 How TCRs Bind pMHC	164
	5.6 What Causes the Restriction in Orientation Imposed on TCR – pMHC Interactions?	171
	5.7 Rationalizing the Purpose of TCR	174
	5.8 Recessive and Dominant Tolerance	176
	5.9 Evolutionary Perspectives	177
	References	179
	6 Fc Receptors	187
	6.1 Introduction	187
	6.2 Fc Receptors—Basic Facts	188
	6.3 Fc Receptor Signaling	192
	6.3.1 Signaling Pathways of Activating Fc Receptors	192
	6.3.2 Inhibitory Signaling Pathways	194
	6.4 Fc Receptor Biology In Vivo	195
	6.4.1 The Role of the Inhibitory Receptor in the Afferent and Efferent Immune Response	196
	6.4.2 FcgRIIB and Dendritic Cells	196
	6.4.3 Loss of the Inhibitory Receptor on B Cells — Horror Autotoxicus	197
	6.4.4 The Role of FcgRIIB in the Efferent Response: Controlling Innate Immune Effector Cell Activation	200
	6.4.5 The Activating Fc Receptors in the Efferent Response	200
	6.4.6 The Missing Piece in the IgG-Puzzle: Identi.cation of FcgRIV	202
	6.4.7 Isotype Speci.c Fcg- Receptor Engagement and Differential Regulation by FcgRIIB	203
	6.4.8 The Effect of Cytokines on FcR Expression	204
	6.5 Summary	206
	References	206
	7 Self and Nonself Recognition by Coreceptors on B Lymphocytes: Regulation of B Lymphocytes by CD19, CD21, CD22, and CD72	213
	7.1 Introduction	213
	7.2 Regulation of B Cells by CD19/CD21 Complex	214
	7.3 Regulation of B Cells by CD22	220
	7.4 Regulation of B Cells by CD72	224
	7.5 Self and Nonself Recognition by Coreceptors on B cells	226
	References	227
	8 Co-Receptors in the Positive and Negative Regulation of T- Cell Immunity	235
	8.1 Introduction	235
	8.2 Positive Co-stimulatory Molecules	238
	8.3 Negative Co-stimulatory Molecules	243
	8.4 Conclusion	250
	References	251
	Index	260