Biology Reference
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have been multiple attempts to find a common marker that can be used
in both species. Hayakawa and colleagues
[46]
were able to differentiate
mouse NK maturation stages through the expression of the TNF receptor
family member CD27, also expressed in humans, and CD11b. Four matu-
ration stages have been identified: CD11b
low
CD27
low
, CD11b
low
CD27
high
,
CD11b
high
CD27
high
, and CD11b
high
CD27
low
. CD11b
low
CD27
high
NK cells are
located in lymph nodes (LN), spleen, liver, and BM; whereas CD11b
high
CD-
27
low
are located in the spleen and liver and represent the main NK subsets
in the peripheral blood and lung. In humans, a CD27
high
subset is found
within the CD56
bright
NK population, while CD27
low
is mainly expressed
on peripheral blood CD56
dim
NK cells. Similar to CD56
bright
, CD11b
low
CD-
27
high
produce higher levels of cytokines than CD11b
high
CD27
low
. However,
CD11b
low
CD27
high
NK cells also display strong cytotoxic function, differ-
ent from CD56
bright
. Nevertheless, owing to organ location and function,
CD11b
low
CD27
high
and CD11b
high
CD27
low
correspond to CD56
bright
and
CD56
dim
, respectively. Additionally, there is a paucity of NK cells present
in the mouse LN, whereas human CD56
bright
NK cells are relatively abun-
dant in human LN. As CD56
bright
NK cells are poorly lytic and thought to
predominantly mediate effector functions through production of cytokines
such as IFN-γ, this suggests a significant divergence between the species
with regard to possible immunoregulatory roles of NK cells.
336
Resting mouse NK cells, in comparison with fresh isolated human NK
cells, have much lower cytotoxic functions, which necessitates the stimula-
tion of mouse NK cells to reach functional capabilities. The generation of
inbred mice as well as the housing conditions (specific-pathogen-free) may
account for the poor lytic function of resting mouse NK cells. Additionally,
mouse NK cells cultured
in vitro
survive for a short period of time compared
with human NK cells, which can be maintained for longer with stable KIR
expression
[47]
. These results would suggest that similar effects may occur
in vivo
by which mouse NK cell therapies may underestimate potential effi-
cacy because of their short-lived nature.
Nevertheless, despite these differences, because of the mouse's small size
and shorter life and the accessibility to reagents and multiple transgenic
and deficient models, mouse research represents a necessary platform to
further advance our understanding of NK biology and provides insightful
information for the clinical application of NK-based immunotherapy in
human diseases.
Studies in mouse models have allowed for the analysis of multiple param-
eters involved in NK maturation, activation, and function, which provide
essential data to understand NK biology and have a strong potential for
clinical/human translation. Mouse models have been invaluable in allow-
ing for the identification of those molecules relevant for NK activation
or suppression with the discovery of the Ly49 family members
[14]
. For
example, IL-15 was first demonstrated to be required for NK maturation
and activation when IL-15-deficient mice showed profound NK defects
compared with IL-2-deficient mice
[48]
. However, it was also shown that
the IL-15 requirement could be overridden after infection. Studies using
IL-15- and IL-15Rα-deficient mice showed the NK population could be
restored upon CMV infection
[49]
. Studies in mice also allowed the
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