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INTRODUCTION

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The fetus and neonate are more vulnerable than older children and adults to severe infection with pathogens, including pyogenic bacteria, fungi, viruses, and intracellular protozoa.1 Although this vulnerability indicates substantial limitations in innate and adaptive immunity in prenatal and early postnatal life, the mechanistic basis for these is only partially understood. Hematopoietic stem cell transplantation also provides compelling evidence for impairment of neonatal T-cell and natural killer (NK) cell immunity: Allogeneic hematopoietic cell transplantation with cord blood is associated with a significantly lower risk of acute graft-vs-host disease—a disease that is mainly mediated by donor-derived naïve T cells—compared to bone marrow and peripheral blood transplants containing adult T cells.2

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DENDRITIC CELLS AND ANTIGEN PRESENTATION

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CD11c+ dendritic cells (DCs) are myeloid-derived cells that participate in antigen presentation to T cells and B cells and also produce critical cytokines that shape adaptive immune responses. For example, the cytokines interleukin (IL)-12 p70, a heterodimer of the IL-12/IL-23 p40 subunit and IL-12 p35, and IL-15, which are produced by DCs, not only provide early innate immune protection but also promote the development of an adaptive immune response dominated by T helper 1 (Th1)–type effector CD4 T cells that produce interferon (IFN)-γ. Plasmacytoid dendritic cells (pDCs) are a distinct DC population that, at rest, lacks the characteristic dendrite-like protrusions of CD11c+ DCs and is found in lymphoid tissue, the circulation, and certain sites of tissue inflammation (eg, the skin in herpes simplex virus [HSV] infection). Activated pDCs are an important source of type I IFNs, which include multiple types of IFN-α and a single type of IFN-β. These type I IFNs are an important source of early and systemic innate antiviral immunity and enhance the later adaptive immune response, including Th1 differentiation from naïve CD4 T-cell precursors. DCs are activated by their recognition of conserved structures of microbial pathogens by toll-like receptors (TLRs), C-lectin-type receptors (CLRs), retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), and nucleotide binding domain and leucine-rich repeat-containing receptors (NLRs)3 as well as other stimuli.

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DCs in Tissues

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The colonization of CD11c+ DCs in extralymphoid and lymphoid tissues is developmentally regulated and occurs independently of exposure to inflammatory mediators. Immature CD11c+ DC lineage cells are found in the interstitial regions of solid organs, including the kidney, heart, pancreas, and lung, but not the brain, by 12 weeks of gestation; their numbers progressively increase through 21 weeks’ gestation.3 Epidermal DC-like cells that express the human MHC (major histocompatibility complex) class II isotype, HLA-DR (human leukocyte antigen DR), are found in the skin earlier, at 7 weeks’ gestation, and are probably derived from CD45+ HLA-DR+ cells that enter the epidermis, extensively proliferate, and then acquire the characteristic features of Langerhans DCs, including CD1c, langerin, and CD1a in a stepwise manner.4

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Circulating and Monocyte-Derived DCs

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