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CHAPTER 17 Cytotoxic T Lymphocytes and Natural Killer Cells 257

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haplotype that supplies more KIR ligand than a matched recipient are found within the CXCR6 CD49a liver ILC1 pool. These
would provide. Hence it would yield a stronger graft-versus- liver-resident ILC1 are transcriptionally and phenotypically
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leukemia (GvL) effect. Indeed, mice treated with alloreactive distinct from conventional NK cells, and their role in mam-
NK cells tolerate 30 times the lethal dose of mismatched bone malian immunity is still to be elucidated. Interestingly, ILC1
marrow cells without developing GvHD, and alloreactive NK cells do not migrate in steady state. Thus how they are activated in a
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eradicated human acute myeloid leukemia (AML) transplanted hapten-specific manner during CHS remains to be determined.
into immune-deficient mice. Retrospective studies on patients Furthermore, inflammation, in general, and especially the cyto-
with AML and acute lymphoblastic leukemia (ALL) who received kines IL-12, IL-18, type I IFN, and the NLRP3 inflammasome, are
haploidentical grafts revealed that transplants with alloreactive critical for the generation of hapten-dependent memory NK-cell
NK cells showed better engraftment and GvHD protection and development. 24
less relapse. 29
These studies suggest that therapeutic treatment with alloreac- INTERACTIONS OF CTL AND NK CELLS
tive NK cells will be effective in eliminating residual cancer cells IN THE IMMUNE RESPONSE
following frontline treatments or in preventing cancer relapse.
Feasibility studies have shown that the production of clinical-grade Although studies of CTLs and NK cells in isolation have greatly
cultured human NK cells is possible and that the transferred advanced our understanding of their functions, it is obvious
cells persist for some time in the patient. An alternative strategy that these immune cells function in a system that depends on
is the use of monoclonal antibodies (mAbs) directed against a numerous interactions between the various cell types at multiple
particular inhibitory KIR. Preclinical studies suggest that blockade levels. In the case of cytotoxic cells, these immunomodulatory
of the inhibitory KIR enhances antitumor activities of the interactions are becoming increasingly appreciated (see Fig. 17.2).
endogenous NK cells, providing a rationale for ongoing clinical In particular, it has become apparent that NK cells and DCs
trials to test this approach. 18,29 interact specifically to promote some outcomes, such as matura-
tion and priming of NK cells. CTL activation by mature DCs is
NK-Cell Memory influenced directly by NK cell–derived IFN-γ and indirectly
through the role of NK cells in promoting a Th1 response in
CD4 T cells (Chapter 16). 30
ON THE HORIZON Increasing evidence has emerged to implicate DC–NK cell
Clinical Trials of Transferred Alloreactive Natural cross-talk in various aspects of the immune response. DCs produce
Killer (NK) Cells a variety of cytokines that modulate NK-cell behavior, including
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IL-12, IL-15, IL-18, and IFN-α. The outcome of these interac-
Adoptive transfer of cultured clinical grade NK cells has proven feasible tions for the DC depends on its maturity; immature DCs are
and well tolerated by patients and is a promising therapy to limit killed by NK cells, whereas mature DCs are resistant to lysis.
relapse in patients with cancer.
A treatment regimen comprising preconditioning with chemotherapeutic The interactions of mature DCs and NK cells would be expected
reagents followed by alloreactive NK cells and interleukin-2 (IL-2) to occur at the site of infection, where DCs provide inflammatory
administration has been examined. stimuli for NK cells. Type I IFN production by DCs promotes
Therapeutic blockade of inhibitory NK-cell receptors using anti–killer MHC-I upregulation by CTLs and their protection from NK-cell
immunoglobulin-like receptor (KIR) monoclonal antibodies is undergoing killing during viral infections. The other site of encounter is the
clinical trials for their efficacy in boosting NK cell–mediated killing of lymph node, where, during an immune reaction, NK cells are
cancer cells.
recruited by chemokines and interact with mature DCs and CD4
T cells to induce a Th1 response. This process requires IFN-γ
production from NK cells (see Fig. 17.2). 30
During the last decade several studies have described the ability NK cell–CTL interactions are also important in generating
of NK cells to generate a “memory” response to pathogens and an immune response to tumors that are, in general, poorly
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antigens. The original documentation of NK-cell memory was immunogenic. DCs that are matured in vitro by NK cells show
in a cutaneous contact hypersensitivity (CHS) model. CHS strongly enhanced ability to induce Th1 and CTL responses,
involves the sensitization by skin exposure to the haptens including cytokine secretion. IFN-γ, in particular, is very impor-
2,4-dinitrofluorobenzene (DNFB) and oxazolone (OXA), fol- tant in the rejection of primary tumors and the formation of
lowed by rechallenge at a previously unexposed site, such as CTL memory to tumors. It is also likely that killing by NK cells
the ear, several days later. NK cells accumulated in the ears of and CTLs provides DCs with increased access to tumor antigens
T/B cell– deficient mice upon DNFB rechallenge, and this was and promotes further adaptive immunity. Using DCs to harness
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dependent on the adhesion molecules of the selectin family. the helper function of NK cells as well as the cytotoxic functions
The concept of NK-cell memory has since been extended to of both CTLs and NK cells offers therapeutic promise and is
viral responses, including MCMV, influenza, vaccinia virus, currently being tested in a variety of cancers.
HSV, HIV, and vesicular stomatitis virus where NK cells from
mice preexposed to the virus were more efficiently activated and EVASION OF THE CYTOTOXIC RESPONSE
prolonged survival from lethal infection compared with naïve
NK cells. Although the interaction between Ly49H and the viral Viruses
protein m157 is required for the memory response elicited by As one principal function of CTL and NK cells is the control of
MCMV infection, the NK cell receptor–ligands combinations viral infections, it is not surprising that viruses have strategies
involved in the other viral models are not established. In most to interfere with the host response (Chapter 25). The multiplicity
settings, the NK-cell memory response is specific to the antigen of these evasion strategies indicates that this is an essential step
(hapten or virus), and the memory NK cells or their precursors for long-term viral persistence.