Dendritic cells as prototypes of antigenpresenting cells

Dendritic cells, macrophages and B cells represent the main antigen-presenting cells of the immune system. Dendritic cells (DC) are the most potent inducers of specific immune responses and are considered essential for the initiation of primary antigen-specific immune reactions. DC precursors migrate from the bone marrow towards the primary lymphatic organs and into the submucosal tissue of the gut, the genitourinary system and the respiratory tracts. They are able to pick up and process soluble antigens and migrate to the secondary lymphatic organs, where they activate antigen-specific T cells. Because DC have a crucial role in adaptive immunity, there is an increasing interest in using dendritic cell to induce or expand HIV-specific T-cells. DC from HIV-infected patients have been purified, incubated with inactivated, non-infectious HIV particles and subsequently used for vaccination (Lu

DC represent a heterogeneous family of cells with different functional capacities and expression of phenotypic markers, depending on the local microenvironment and the stage of maturation. Immature DC have the capacity to pick up and process foreign antigens, but do not have great T cell stimulatory capacities. However, mature DC show a predominant immunostimulatory ability. DC in tissues and Langerhans' cells, which are specialized DC in the skin and mucosal areas, represent a more immature phenotype and may take up antigen. Once these DC have taken up the antigen, they migrate to the lymphoid tissues where they develop a mature phe-notype. Viruses may induce plasmacytoid DC to produce substantial amounts of IFN alpha with antiviral activity by stimulating Toll-like receptors (TLR) (Beignon

2005) therefore linking the innate to the adaptive immune system.

The stimulation of CD8 T-lymphocytes and the formation of antigen-specific cytotoxic T cells (CTL) depend on the presentation of a peptide together with MHC class I antigens. DC may become infected with viruses, for instance influenza. Viral proteins are then produced within the cytoplasm of the cell, similar to cellular proteins, then degraded to viral peptides and translocated from the cytosol into the endoplasmic reticulum, where they are bound to MHC class I antigens. These peptide-MHC class I complexes migrate to the DC surface. Interestingly, efficacy of presentation of viral antigens is comparable regardless whether DC themselves or productively infected or not. An alternative way, where DC acquire exogenous antigens for MHC class I presentation from e.g. infected cells is termed cross-presentation and may be relevant for both classical and plamacytoid DC in HIV immunity (Rawson 2007, Hoeffel 2007).

The number of specific antigen-MHC class I complexes is usually limited and must eventually be recognized by rare T-cell clones, up to a ratio of 1:100.000 or less. The T-cell receptor (TCR) may display only a low binding affinity (1mM or less). The high density of co-stimulatory molecules on the DC surface, however, enhances the TCR-MHC: peptide interaction allowing efficient signaling to occur through the T-cell and resulting in proliferation (clonal expansion) of the T-cell. Virus-infected cells or tumor cells often do not express co-stimulatory molecules, and thus may not be able to induce a clonal expansion of effector cells. This underscores the importance of having a highly specialized system of antigen-presenting cells, i.e., DC, in operation to prime T-cells to expand and proliferate initially.

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