Dendritic cells
Dendritic cells (DCs), originally identified by Steinman and his colleagues (1972) represent the pacemakers of the immune response. They are crucial to the presentation of peptides and proteins to T and B lymphocytes and are widely recognized as the key antigen presenting cells (APCs). They are critical for the induction of T cell responses resulting in cell-mediated immunity (CMI). The T cell receptors (TCRs) on T lymphocytes recognize fragments of antigens (Ags) bound to molecules of the major histocompatibility complex (MHC) on the surfaces of APCs. The peptide binding proteins are of two types, MHC class I and II, which interact with and stimulate cytotoxic T lymphocytes (CTLs) and T helper cells (Ths), respectively. On entry into APCs, Ags are processed, spliced into peptides in the cytosol and then reexpressed on the cell surface linked to MHC proteins. When bound to MHC class I molecules, CTLs are generated and activated and cells in tissues expressing the Ags (e.g. virus infected cells, cancer cells) are recognised and destroyed. Antigens reexpressed on the cell surface linked to MHC class II molecules interact with Th cells which when activated have profound immune-regulatory effects. Thus, DCs play a key role in host defenses and a crucial role in putative anti-cancer immune responses.
Introduction
An important advance in DC biology, within the past few years, has been the ability to propagate in vitro large numbers of DCs, using defined growth factors. One of the most important findings is that DCs are not a single cell type, but a heterogeneous collection of cells that have arisen from distinct, bone marrow-derived, hematopoietic lineages. To date, at least three different pathways have been described. The emerging concepts are that each pathway develops from unique progenitors, that particular cytokine combinations drive developmental events within each pathway and that cells developing within a particular pathway exhibit distinct specialized functions.
The ability to propagate DC subtypes, at various stages of development in vitro, from early progenitors has been critical in assessing the developmental and functional characteristics of DCs. Together with in situ histochemical analyses and genetically modified animal models, in vitro studies have shown that the earliest DC progenitors/precursors are released from the bone marrow and circulate through the blood and lymphoid organs ready to receive differentiation signals.
Several studies have been carried out suggesting that there are different pathways for the formation of mature DCs from CD34+ or other primitive progenitors. Each pathway differs in terms of progenitors and intermediate stages, cytokine requirements, surface marker expression and, probably most importantly, biological function.
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