CTLs express on their surface molecules of a transmembrane protein, the death activator designated Fas ligand (FasL). Most potential CTL targets express a receptor for FasL designated Fas.
When cytotoxic T cells recognize (bind to) their target,
· they produce more FasL at their surface.
· This binds with the Fas on the surface of the target cell leading to its death by apoptosis
· Fas and the TNF receptor are integral membrane protein with their receptor domains exposed at the surface of the cell
· binding of the complementary death activator (FasL and TNF respectively) transmits a signal to the cytoplasm that leads to
· activation of caspase 8
· caspase 8 (like caspase 9) initiates a cascade of caspase activation leading to
· phagocytosis of the cell.
Positive and negative selection in the thymus is normal is lpr mice - mice with non functional Fas proteins. Therefore, Fas does not affect this system. In the case of positive selection, when T cells are being educated in the thymus to recognize self MHC, T cells that fail this selection die by lack of survival signal. Thus, Fas mediated apoptosis does not play a role here.
In the case of negative selection, mutant lpr and gld mice that have nonfunctional Fas answered this question. Researchers did not observe an affected T cell repertoire in these mice, therefore negative selection still occured as it does in wild type mice. Thus, Fas/FasL interactions do not initiate apoptosis during negative selection.
Regarding B cells, the situation is not so clear, however it is thought that apoptosis involves the mitochondrial pathway
Activated T cells coexpress Fas and FasL. This allows the T cells to be sensitive to FasL either on the same cell or on another cell. Activating B cells induces the expression of Fas, making them susceptipble to cell death via the Fas system. In mice and in humans with wild type Fas, Fas mediated cell death eliminates self reactive T cells in the periphery and activated T cells after the immune response has done its job.
Elimination of self reactive T cells
While T cells are exposed to self antigen during education in the thymus, not every possible self protein peptide is presented; it is possible for self reactive T cells to make it out of the thymus into the periphery. These cells are actively killed by the Fas system. Researchers know Fas plays a role in deleting self reactive cells because a lack of Fas function confers autoimmunity.
Elimination of activated T cells
The immune system works by controlling the number of cells through growth and death. Part of the reason why the immune system is so successful is due to overproduction of cells and then selective killing of cells to leave the very best ones. Apoptosis via the Fas/FasL system is necessary to decrease the activated lymphocyte population in the periphery after the immune response has killed off the pathogen.