Review Article | Published:

Cytotoxic T lymphocytes: all roads lead to death

Abstract

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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Acknowledgements

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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Glossary

MICROTUBULE-ORGANIZING CENTRE

A region of the cell from which microtubules grow. Motor proteins that are associated with the microtubles are responsible for the directed movement of organelles in the cytoplasm.

LPR MICE

These are naturally occurring mutants that bear a deletion of the Fas gene.

GLD MICE

These mice have a naturally occurring mutation of Fas ligand that causes a generalized lymphoproliferative disease.

CASPASES

A family of cysteine proteinases that are involved in the initiation and effector stages of apoptosis.

TYPE I/II SYSTEM

A classification of cells on the basis of their sensitivity to FAS-mediated killing. Type I cells recruit caspase-8, which results in the subsequent cleavage of caspase-3. Type II cells activate caspase-3 through a mitochondria-dependent step.

GRAFT-VERSUS-HOST DISEASE

The immune reaction against a graft recipient that is mounted by immune-competent cells of a graft.

IMMUNOLOGICAL SYNAPSE

A distinct region formed at the contact zone between the cytotoxic T lymphocyte and target cell due to the specific reorganization of cell-surface membrane proteins.

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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.