Plasmacytoid Dendritic Cells

This book provides a systematic review of the development, function, and patho-physiologic role of plasmacytoid dendritic cells (pDCs) in humans. The chapters of the book discuss the origin and discovery, hematopoietic development as well as molecular regulation of pDCs in the context of immune activation as well as immune tolerance. It also discusses the role of pDCs in human diseases, including infections, autoimmune/inflammatory diseases, cancers and metabolic disorders, and opportunities for pDC‐targeting therapies in these varied clinical contexts. Preface 5 Contents 7 Chapter 1: Discovery of a New Dendritic Cell Subset 10 1.1 A Brief Biosketch of the Immune System 10 1.2 Discovery of the Conventional Dendritic Cells 11 1.3 The Search for a Professional Interferon Producer 13 1.4 A New Dendritic Cell Subset Is the ``Professional Interferon Producer ́ ́ 14 1.5 Conclusion 15 References 16 Chapter 2: Origin and Transcriptional Identity of Plasmacytoid Dendritic Cells 20 2.1 FLT3-Receptor Dependence and Shared Origin of cDCs and pDCs 20 2.2 Myeloid Versus Lymphoid Origin of pDCs 21 2.3 Transcriptional Program for pDC Commitment and Function 23 2.3.1 E2-2 24 2.3.2 IRF8 25 2.3.3 Regulators of Functional Identity 26 2.4 Localization and Migration of pDCs 27 2.5 Conclusions 28 References 28 Chapter 3: Activation and Functions of Plasmacytoid Dendritic Cells 34 3.1 Toll-like Receptor Activation and Signaling in pDCs 34 3.2 Cell Biology of Endosomal TLR Localization in pDCs 36 3.3 The Cytokine Response in pDCs in Response to TLR Activation 37 3.4 Antigen Presentation by pDCs 41 3.5 Cell Biology of Differential pDC Response to TLR Activation 42 3.6 Cellular Metabolism of Activated pDCs 45 3.7 The Elusive Role of IL-3 in pDC Immunobiology 47 3.8 Functional Heterogeneity of Plasmacytoid Dendritic Cells 48 3.9 Regulators of Type I IFN Induction by pDCs 49 3.9.1 ILT7 50 3.9.2 BDCA2 50 3.9.3 Siglec-H 51 3.10 Other Regulatory Surface Molecules in pDCs 52 3.11 Endocannabinoids and Cannabinoid Receptors 54 3.12 Metabolite Transporters and Receptors 55 3.13 Effect of Biological Sex on pDC Activation 55 3.14 Conclusions 56 References 57 Chapter 4: Plasmacytoid Dendritic Cells and Infections 70 4.1 RNA Viruses and pDCs 70 4.2 Human Immunodeficiency Virus and pDCs 72 4.3 PDCs and the Novel Coronavirus SARS-CoV-2 75 4.4 DNA Viruses and pDCs 75 4.5 PDCs in Bacterial Infections 77 4.5.1 Extracellular Bacteria and pDCs 78 4.5.2 Intracellular Bacteria and pDCs 79 4.6 PDCs in Malaria 81 4.7 PDCs in Fungal Infections 83 4.8 Conclusions 84 References 84 Chapter 5: Plasmacytoid Dendritic Cells in Autoimmunity 93 5.1 Systemic Lupus Erythematosus 94 5.2 Psoriasis 96 5.3 Systemic Sclerosis 100 5.4 Sjogren ́s Syndrome 102 5.5 Role of pDCs in Other Major Rheumatological Disorders 102 5.6 Conclusions 105 References 105 Chapter 6: Plasmacytoid Dendritic Cells and Metabolic Disorders 115 6.1 Type 1 Diabetes Mellitus 116 6.2 Obesity and Type 2 Diabetes 116 6.3 Cardiovascular Components of Metabolic Syndrome 119 6.4 Fatty Liver Disease and Hepatic Metaflammation 120 6.5 A Potential Pathogenic Continuum for Autoimmune Diseases and Metabolic Syndrome 121 6.6 Conclusions 123 References 123 Chapter 7: Tolerogenic Functions of Plasmacytoid Dendritic Cells 129 7.1 Thymic pDCs and Central Tolerance 130 7.2 Mucosal Tolerance Driven by pDCs 131 7.3 Tolerogenic pDCs and Tissue Transplantation 133 7.4 Suppression of Anti-cancer Immunity 135 7.5 Conclusions 135 References 136 Chapter 8: Plasmacytoid Dendritic Cells and Cancer 141 8.1 Plasmacytoid Dendritic Cells and the ``Cancer-immunity Cycle ́ ́ 141 8.2 Leukemogenesis and pDCs 142 8.3 Breast Cancer and pDCs 143 8.4 Ovarian Carcinoma and pDCs 145 8.5 PDCs in Neoplasmas of the Aero-digestive Tract 145 8.6 Malignant Melanoma and pDCs 147 8.7 Conclusion 148 References 149 Chapter 9: Therapeutic Targeting of Plasmacytoid Dendritic Cells 154 9.1 Targeting pDCs and Type I IFNs in Autoreactive Inflammation 154 9.1.1 Targeting Endosomal TLRs in pDCs 154 9.1.2 Biologics Targeting pDCs and Type I IFNs 158 9.2 Targeting pDCs in Infection 158 9.3 Targeting pDCs in Cancer 159 9.3.1 Targeting Endosomal TLRs and Other pDC-intrinsic Molecules 159 9.3.2 PDC-Based Vaccines for Cancer 161 9.4 Conclusion 161 References 162 Abbreviations 168 This book provides a systemic review of the development, function, and role of plasmacytoid Dendritic Cells (pDCs) in human diseases. The chapters of the book discuss the origin and discovery, heterogeneity, development, and transcriptional regulation of pDCs. It also discusses the role of pDCs in human diseases, including cancers, metabolic disorders, and autoimmune/inflammatory diseases, and opportunities for pDCtargeting therapies in these diseases. It also highlights the current understanding of pDC involvement in autoimmunity and alloreactivity and opportunities for pDCtargeting therapies in the disorders. Lastly, it reviews the experimental methodologies and animal models that are used to explore the functions of pDCs