Activation of a T-cell is a complex, tightly regulated process. This is necessary in order to ensure that T-cell activation is directed only against pathogens and not against body tissues. Furthermore, increased complexity decreases the likelihood that a microorganism can evolve mechanisms to subvert T-cell activation. T-cell activation takes place in the peripheral lymphoid organs. However, before this can occur, antigen is processed and presented in association with MHC molecules, and the antigen is then transported from the site of infection to the peripheral lymphoid organs and presented to T-cells. The processing, transportation and presentation of antigen are performed by antigen-presenting cells, the most important and efficient of which are dendritic cells. Dendritic cells are mandatory for the initiation of a primary immune response against a new pathogen, although both dendritic cells and non-professional antigen-presenting cells, such as macrophages and B-cells, are able to initiate secondary (memory) responses against reinfecting organisms.
Dendritic cells (Banchereau and Steinman, 1998)
These are generated in the bone marrow but are subsequently widely distributed throughout the tissues, typically in association with epithelial surfaces. When viewed by phase-contrast microscopy, dendritic cells extend long, delicate, motile processes in all directions. In peripheral tissues, so-called 'immature' dendritic cells have poor T-cell stimulatory activity. Instead, they act as sentinels, constantly sampling the surrounding tissues for pathogens. Immature dendritic cells accumulate foreign antigens in their surroundings by macropinocytosis of soluble antigens and phagocytosis of particulate antigens and microorganisms. These processes are so efficient that dendritic cells can initiate immune responses with pico- and nanomolar concentrations of antigens, compared with the micromolar concentrations required by non-professional antigen-presenting cells, such as B-cells and macrophages.
After a dendritic cell captures a pathogen-associated antigen, its sampling function declines and, instead, it starts to process pathogenic antigens and present them in association with MHC molecules on its cell surface. Endocytosed antigens are presented in association with MHC class II molecules, while endoge-nously produced antigen, e.g. from a virus infecting the dendritic cell, is presented in association with MHC class I molecules. Dendritic cells are able to process and present, in a class I-restricted manner, antigens that do not enter the cytosolic compartment, e.g. viruses unable to infect dendritic cells. However, the mechanism for this is unclear. As antigens are processed and expressed, dendritic cells up-regulate surface expression of T-cell co-stimulatory molecules, such as CD40 and B7. Dendritic-cell maturation is also associated with secretion of cytokines and chemotactic cytokines (chemokines), which recruit macrophages, granulocytes, NK cells and more dendritic cells to counter the invading pathogen.
After processing and presenting antigen, dendritic cells bearing processed antigen migrate from the site of infection to the T-cell areas of local lymph nodes. There migration stops and they interact with T- and B-cells to initiate an immune response. Mature dendritic cells are extremely potent activators of T-cells, with a single dendritic cell being able to activate 100-3000 T-cells. This is because of the high density of MHC, co-stimulatory and adhesion molecules expressed by dendritic cells and the secretion of cytokines that profoundly influence T-cells, e.g. IL-12.
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