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Cytotoxic T lymphocytes: all roads lead to death


Cytotoxic T lymphocytes (CTLs) provide potent defences against virus infection and intracellular pathogens. However, CTLs have a dark side — their lytic machinery can be directed against self-tissues in autoimmune disorders, transplanted cells during graft rejection and host tissues to cause graft-versus-host disease, which is one of the most serious diseases related to CTL function. Although this duplicitous behaviour might seem contradictory, both beneficial and detrimental effects are the result of the same effector proteins. So, an understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies.

Key Points

  • Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells provide protection against a wide variety of pathogens.

  • Key components of the killing machinery are found in the cytoplasmic granules of CTLs and NK cells.

  • The mechanism of killing involves directed exocytosis of cytolytic effectors, such as perforin and granzymes.

  • Granzyme B initiates apoptosis through the cleavage and activation of caspases.

  • Granzyme B gains access to the target cell by receptor-mediated endocytosis.

  • Perforin facilitates the uptake and release of granzyme B into the cytoplasm of the target cell.

  • Other substrates for granzyme B indicate that it has an effect on the mitochondrial and caspase-independent pathways to cell death.

  • Other granzymes and cytoplasmic proteins can also act to induce target-cell destruction.

  • Viruses have evolved numerous strategies to inhibit apoptosis and CTL- and NK-cell-mediated killing.

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We dedicate this review to the memory of A. Greenberg: sometimes a collaborator, often a competitor, always a friend. R.C.B. is an Alberta Heritage Foundation for Medical Research Scientist, Canadian Institute Health Research Distinguished Scientist and Howard Hughes International Research Scholar. M.B. is an Alberta Heritage Foundation for Medical Research Scholar.

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Figure 1: Engagement of FAS (CD95) on a target cell with CTL-expressed FAS ligand (FASL; CD178) results in apoptotic death.
Figure 2: Pathways of entry for granzyme B.
Figure 3: Pathways to cell death that are initiated by granzyme B.
Figure 4: Virus-encoded inhibitors of apoptosis and CTL-mediated killing.