Apoptosis, inflammatory bowel disease and carcinogenesis: Process of apoptosis of target cells (Part 2)
Step 3: Delivery of lethal hit mediated by perforin and granzyme B and/or Fas-FasL complex. During this process, CTLs develop specific membrane-bound cytoplasmic granules that contain numerous macromolecules, including a membrane pore-forming protein called perforin or cytolysin; enzymes frequently called granzymes that contain reactive serines in their active sites; and proteoglycans. In addition, CTLs share with other activated T lymphocytes (TLs) surface expression of FasL, which can deliver apoptosis-inducing signals to target cells expressing the Fas protein. Moreover, CTLs share with other effector TLs the ability to transcribe and secrete cytokines and other proteins upon activation, mainly tumour necrosis factor (TNF), interferon-y (IFN-y), lymphotoxin, and, to a lesser degree, interleukin (IL)-2. Studies of CTL-mediated killing of target cells in vitro had shown that granule exocytosis-depend-ent (ie, perforin/granzyme-mediated) killing and granule exocytosis-independent (ie, FasL-mediated) killing were redundant.
More recent reports have suggested that perforin and granzyme are the key mediators of CTL function in immune responses to intracellular microbes. In contrast, the Fas pathway appears to be more important for immune regulation than for CTL functions (ie, for controlling excessive lymphocyte activation, particularly against self-antigens).
The lethal hit is initiated by exocytosis of the granule contents onto the membrane of the target cell. As a consequence of granule content exocytosis, perforin, present as a monomer in the granule, comes in contact with extracellular levels of calcium (typically 1 to 2 mM) and undergoes polymerization. Polymerization of perforin leads to the formation of a large water-filled channel that preferentially occurs in a lipid bilayer, such as the plasma membrane of the target cell. Find best deals online – cialis super active online only here can be available every time you visit.