Targeting dendritic cells for priming cellular immune responses

Abstract

The cardinal role of dendritic cells (DC) in priming adaptive immunity and in orchestrating immune responses against all classes of pathogens and also against tumors is well established. Their unique potential both to maintain self-tolerance and to initiate protective immune responses against foreign and/or dangerous structures is based on the functional diversity and flexibility of these cells. Tissue DC lining antigenic portals such as mucosal surfaces and the skin are specialized to take up a wide array of compounds including proteins, lipids, carbohydrates, glycoproteins, glycolipids and oligonucleotides, particles carrying such structures and apoptotic or necrotic cells. This process is facilitated by specialized receptors with high endocytic capacity, which provides potential targets for delivering designed molecules. The best route for targeting B- and/or T cell epitopes, however, is still the subject of intense investigation. Immature DC, which reside in various tissues, can be activated by pathogens, stress and inflammation or modified metabolic products, which induce mobilization of cells to draining lymph nodes where they act as highly potent professional antigen presenting cells. This is brought about by the ability to present their accumulated intracellular content for both CD4+ helper (Th) and CD8+ cytotoxic/cytolytic T lymphocytes (Tc/CTL). Engulfed proteins are processed intracellularly and their peptide fragments are transported to the cell surface in the context of major histocompatibility complex encoded class I and II molecules for presentation to Th cells and CTLs, respectively. The T cell priming capacity of DC, however, depends not only on antigen presentation but also on other features of DC. Human monocyte-derived DC provide an excellent tool to study the internalizing, antigen-presenting and T cell-activating functions of DC at their immature and activated differentiation states. These biological activities of DC, however, are highly dependent on their migratory potential from the peripheral non-lymphoid tissues to the lymph nodes, on the expression of adhesion molecules, which support the interaction of DC with T lymphocytes, and the cytokines secreted by DC, which polarize immune responses to Th1-mediated cellular or Th2-mediated antibody responses. These results altogether demonstrate that monocyte-derived DC are useful candidates for in vitro or in vivo targeting of antigens to induce efficient adaptive immune responses against pathogens and also against tumors.

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

“…Our data on the rapid activation-driven upregulation and downregulation of the channel suggested direct transcriptional control of Nav1.7 expression. Transcriptional regulation of ion channel expression has been reported in naive T cells, where the expression of the Ca 2+ -activated K + channel IKCa1 is increased upon activation (32). Elevation of intracellular Ca 2+ concentration in various cell types is one of the most rapid signal transduction events, and the importance, complexity, and impact of Ca 2+ -mediated signaling on the cell cycle of LPS-induced DC have recently been described in mice (33).…”

Developmental Switch of the Expression of Ion Channels in Human Dendritic Cells

“…Differentiation and maturation of DCs from monocytes are linked to marked phenotypic, gene expression, and functional changes (19). The major function of IDCs is to internalize exogenous soluble and particulate tissue components and collect stimuli associated with environmental changes for delivering this molecular information to lymph node T lymphocytes.…”

Processing and Presentation of Exogenous HLA Class I Peptides by Dendritic Cells from Human Immunodeficiency Virus Type 1-Infected Persons

“…It may be possible to attain greater levels of response by long-term priming of naïve T cells (21,26,52) in addition to activation of the limited number of memory CD8 ϩ T cells specific for each peptide. Nevertheless, these data support the use of mDCs as APCs for activation of T-cell responses in immunotherapy trials (15).…”