Open questions: missing pieces from the immunological jigsaw puzzle
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KeywordsNatural Killer Natural Killer Cell Lysosomal Membrane Trigger Cell Death Jigsaw Puzzle
There is nothing more frustrating than reaching the end of a jigsaw puzzle to find that some of the pieces are missing. There are certainly areas of immunology where the same problem applies and despite major advances there are some pieces of the jigsaw that are still missing after many years. When I was asked to think of some of the questions that remain unanswered in the cell biology of the immune system, three leapt to mind. One concerns antigen presentation, another cytotoxic T lymphocyte (CTL)- or natural killer (NK)-cell-mediated killing, and the third a mechanism of apoptosis. Although seemingly disparate, each one of these boils down to a question of how proteins cross membranes to reach the cytoplasm.
The missing step that allows 'cross-priming'
How do cytotoxic cells avoid self-destruction?
A chicken-and-egg problem in apoptosis
The third problem concerns apoptosis. One recently proposed pathway of caspase-independent apoptosis  suggests that the initial event triggering cell death is rupture of the lysosomal membranes releasing cathepsins that can be active in the cytoplasm. This pathway is thought to provide an additional mechanism for triggering apoptosis. There is something of a chicken-and-egg problem, however, as it is difficult to be sure that lysosomal breakdown is the initiating event rather than a consequence of rapid cell death. However, the key question that remains is how the membrane is ruptured to allow the proteins to escape into the cytoplasm.
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