Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 331

NK cell memory

The capacity for immune memory has long been considered a property
of T and B cells, yet our enhanced understanding of NK cell function and
the receptor-ligand interactions involved has led to studies that demon-
strate that NK cells may also be able to mediate immune memory. NK cells
have been shown to have hapten-specific memory in mice [38] . Mice that
lacked both T and B cells still mounted a strong contact-hypersensitivity
response and depletion of NK cells abolished the response, suggesting that
NK cells are capable of adaptive immune responses. Furthermore, hapten-
specific memory was transferrable. Sun and colleagues [39] were the first to
demonstrate NK-cell-mediated viral immune memory. During CMV infec-
tion in mice, NK cells expressing the activating receptor Ly49H preferen-
tially expand, and persist in high numbers following CMV infection, and
this response is driven through interaction of Ly49H with the viral protein
m157. These NK cells were able to mount a robust response to subsequent
CMV infection after adoptive transfer and had higher IFN-γ mRNA tran-
scripts than naïve Ly49H + NK cells. Additionally, these memory NK cells
could be isolated from mice several months after the initial infection and
were still capable of mounting robust responses. Certain cytokines, IL-12
and IL-18, have also been shown to induce a population of memory NK
cells [40] . Cytokine-activated NK cells were transferred into naïve hosts and
upon restimulation produced significantly more IFN-γ than naïve NK cells.
Characterizing NK cell memory in humans has been far more difficult; how-
ever, there is some evidence to suggest that memory NK cells may exist in
humans. Similar to murine CMV and Ly49H, NK cells that express the acti-
vating receptor NKG2C expand following acute CMV reactivation in trans-
plant recipients [41,42] and coculture with CMV-infected fibroblasts [43] .
These NKG2C + NK cells have been shown to express an inhibitory receptor
for self-HLA; progressively acquire CD57, a marker of NK cell maturity; and
have increased function; thus they may represent a population of long-lived
memory NK cells in humans. Clonal-like expansion of NKG2C + NK cells has
been observed during the acute response to hantavirus and chikungunya
virus and chronic infection with hepatitis B and C only in patients who were
CMV seropositive [44,45] . As a relatively new field of NK cell biology, how
NK cell memory is acquired and maintained in humans still needs to be
characterized.

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Role of NK cells in cancer therapeutics
Human versus mouse NK cells

The invaluable use of mouse models to study NK biology has been unques-
tioned. However, certain caveats should be taken into consideration,
recognizing critical differences between human and mouse NK cells, to
carefully translate mouse data into human research. One of the main dif-
ferences between human and mouse NK cells lies in the phenotype of NK
cells. Mouse NK cells lack expression of CD56, which is the primary marker
used to identify human NK cells and limits translation of mouse NK stud-
ies. Furthermore, the lack of CD56 on mouse NK cells means that there are
also no CD56 bright and CD56 dim subsets, which are present in humans. There