Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Toll-like receptors.

Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

Toll-like receptors: critical proteins linking innate and acquired immunity.

Recognition of microbial infection and initiation of host defense responses is controlled by multiple mechanisms. Toll-like receptors (TLRs) have recently emerged as a key component of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses. TLRs activate multiple steps in the inflammatory reactions that help to eliminate the invading pathogens and coordinate systemic defenses. In addition, TLRs control multiple dendritic cell functions and activate signals that are critically involved in the initiation of adaptive immune responses. Recent studies have provided important clues about the mechanisms of TLR-mediated control of adaptive immunity orchestrated by dendritic cell populations in distinct anatomical locations.

Toll-like receptor control of the adaptive immune responses.

Plasmacytoid dendritic cells (pDCs) are a unique immune cell type that produces a vast amount of interferon (IFN)-α in response to virus-derived DNA and RNA through Toll-like receptor (TLR) 9 and TLR7, respectively. Nucleic acids derived from self-cells also stimulate pDCs to produce IFN-α in certain conditions, and is implicated in the pathogenesis of inflammatory disorders such as lupus and psoriasis. Recent studies have revealed that elaborate vesicular trafficking machinery in pDCs is the key to the prodigious IFN-α production. Upon stimulation, the nucleic acid-sensing TLRs traffic from the endoplasmic reticulum to the endolysosomal compartments together with a multiple membrane-spanning protein UNC93B1 (Unc-93 homolog B1). Aggregated DNA endocytosed by pDCs is retained in early endosomes for an extended period of time or moves to lysosome-related organelles well-equipped with the machinery for IFN-α production. The nucleic acid then meets the TLR in endolysosomes in a way that produces a large amount of IFN-α. Such exquisite ‘receptor transport’ and ‘ligand transport’ systems are vulnerable to pharmacological interventions, the proteasome inhibitor bortezomib, and the tyrosine kinase inhibitor dasatinib, respectively. Elucidating precise molecular mechanisms by which to control vesicular trafficking of TLRs and their ligands in pDCs will reveal new aspects of physiology of vesicular traffic and novel targets to treat pDC-mediated inflammatory disorders.

The Vesicular Traffic System in Plasmacytoid Dendritic Cells as a Target for Immune Regulation

Bone Marrow and Peripheral Blood: Which Is Safe?

近年，樹状細胞（DCs）の強力な抗原提示能を利用したがん免疫療法が注目されている．この療法の中核をなす細胞傷害性T細胞（CTL）を活性化するためには，DC上のMHCクラスIを介してがん関連抗原を提示させる必要がある．そこで筆者らは，DCsへの抗原送達キャリアとしてIgG表面修飾した抗原封入リポソームを開発した．このIgGリポソームはDCs上のFcγレセプターを介して取り込まれ，内封した抗原のMHCクラスIへの抗原提示を誘導することで抗原特異的なCTL誘導を可能とした．本稿では，がん免疫療法における抗原デリバリーキャリアとしてのIgGリポソームの可能性について紹介する．

Development of novel antigen delivery system to dendritic cells using liposome technology in cancer immunotherapy

CD4+CD56+ lineage negative malignancy has recently been considered as plasmacytoid dendritic cell (PDC) leukemia/lymphoma. We investigated immunophenotypic and functional characterizations of PDC leukemic cells in one case. Lineage markers were all negative except partially positive CD11c and positive CD117, indicating malignant cells were leukemic PDCs coexpressing myeloid and progenitor cell surface antigens. Leukemic PDCs cultured with IL-3 increased in size and expression of CD11c, CD40 and HLA-DR, although the cells cultured with IL-2 or GM-CSF showed little proliferation. Furthermore, CD40 ligation after IL-3 stimulation yielded morphological changes such as expression of dendritic process. These findings showed that malignant cells were consistent with leukemic PDCs. However, secretion of interferon-alpha was not detected in leukemic PDCs with the stimulation of CpG ODN or inactivated herpes simplex virus-1.

Norimitsu Kadowaki

Papers

The Vesicular Traffic System in Plasmacytoid Dendritic Cells as a Target for Immune Regulation

Bone Marrow and Peripheral Blood: Which Is Safe?

Development of novel antigen delivery system to dendritic cells using liposome technology in cancer immunotherapy

Derivation of leukemic plasmacytoid dendritic cells coexpressing a progenitor cell surface antigen, CD117, without interferon-alpha production.

Pregnancy course and outcomes of patients with polymyositis and dermatomyositis (PM/DM) managed in a single center