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Cytotoxic T Lymphocytes and Natural
Killer Cells

Stephen L. Nutt, Nicholas D. Huntington

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells The importance of the lytic function of CTLs and NK cells
represent two distinct but functionally related lineages that has been demonstrated in animal models as well as in patients
contribute to pathogen and tumor immunity. Although the with defective cytotoxicity. A number of recessive genetic syn-
approaches by which CTLs and NK cells kill their target cells dromes that affect cytotoxic function have been reported,
and produce immunomodulatory cytokines are quite similar, including familial hemophagocytic lymphohistiocytosis (FHL),
2
the mechanisms by which they recognize their targets are distinctly which results from mutations in the perforin gene. Patients
different. CTLs are CD8 T cells (Chapter 8) that recognize targets with FHL present with severe immunodeficiency that is often
via the interaction of a diverse repertoire of polyclonally rear- associated with uncontrolled viral infections, including cyto-
ranged T-cell receptors (TCRs) (Chapter 4) with a peptide– major megalovirus (CMV), herpes simplex virus (HSV), and Epstein–
histocompatibility complex (MHC) class I complex (Chapter 6) Barr virus (EBV) infections. Similarly, mice genetically deficient
and are components of the adaptive immune response. MHC or depleted for CTLs and NK cells are overtly susceptible to viral
class I molecules are expressed on virtually all cells in the body pathogens and display impaired immunosurveillance. 2
and allow CTLs to scan the tissues for cells expressing foreign With its potent ability to control pathogen-infected and
or cancer-associated peptides. In contrast, NK cells are members malignant cells, it is not surprising that modulation of cytolytic
of the innate immune system (Chapter 3) and use an array of activity is an aim of many immunotherapies (see Part 10). These
invariant activating and inhibitory receptors to control their strategies involve either dampening of CTL function in such
1
activity and specificity. These fundamentally distinct approaches situations as transplantation or autoimmunity or enhancement of
to the recognition of antigen allow for complementary functions, CTL and NK-cell function via vaccination, blocking antibodies to
with CTLs being specialized in detecting cancerous cells or those inhibitory receptors, or cytokine therapy. Tight controls need to
infected with intracellular pathogens, such as viruses, whereas be maintained over these effector cells, as deregulated CTL activity
a prominent function of NK cells is to eliminate those cells can promote autoimmune diseases, hypersensitivity reactions,
where the pathogen or oncogene has impaired MHC class I graft-versus-host disease (GvHD) and transplant rejection. To
expression and/or has induced the expression of stress ligands. maintain the discrimination between killing unwanted or infected
As one of the principal immune-evasion mechanisms of viruses cells and not killing healthy neighboring cells, numerous layers
and tumors is suppression of MHC class I expression, NK cells of regulation operate to control cytotoxic functions.
provide a key line of defense against this strategy.
EFFECTOR FUNCTIONS/MECHANISMS

CLINICAL RELEVANCE KEY CONCEPTS
Functions of Cytotoxic T Lymphocytes (CTLs) Cytotoxic T Lymphocyte (CTLs) and/or Natural
and/or Natural Killer (NK) Cells Killer (NK) Cell Effector Mechanisms

Protective functions include: Cytotoxicity
Host defense against: Killing by the perforin/granzyme pathway
Viruses, including human immunodeficiency virus (HIV), Epstein-Barr Death receptor–mediated apoptosis, including Fas and tumor necrosis
virus (EBV), pox virus, and cytomegalovirus (CMV) factor (TNF)-related apoptosis–inducing ligand (TRAIL)
Bacteria, including Listeria monocytogenes Immune modulation
Parasites, including Plasmodium falciparum and Toxoplasma gondii Inflammatory cytokine production, including interferon (IFN)-γ and TNF
Primary and metastatic tumors Chemokine secretion
Positive regulation of: Immunomodulatory cytokines, including interleukin-10 (IL-10) and
Graft-versus-leukemia (GvL) effect granulocyte macrophage–colony-stimulating factor (GM-CSF)
Placental vascularization by uterine NK cells
Uncontrolled cytotoxicity contributes to
Some autoimmune disease, including diabetes and rheumatoid arthritis
Hypersensitivity reactions Cytotoxicity
Graft-versus-host disease Cytotoxic cells kill their targets via two major pathways: perforin/
Transplant rejection
granzyme–mediated lysis and death receptor–induced apoptosis.

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