Biology Reference
In-Depth Information
Both inhibitory and activating NK receptor (NKR) isoforms have been de-
scribed (Biassoni et al., 1996; Olcese et al., 1997), and several inhibitory and
activating NKRs can be expressed at the cell surface. Inhibitory NKRs harbor
intracytoplasmic immunoreceptor tyrosine-based inhibiting motifs ( ITIMs),
which recruit and activate the protein tyrosine phosphatases SHP-1 and/or
SHP-2 (Vivier and Daeron, 1997). Activating NKRs lack ITIMs and associate
with polypeptides such as DAP-12/KARAP or FcR-g containing immuno-
receptor tyrosine-based activating motifs ( ITAMs), which recruit and activate
the protein tyrosine kinases, Syk and ZAP-70 ( Lanier, 2001; Lanier et al., 1998;
Tomasello et al., 1998). As in humans, NK cells from the mouse also express
receptors that recognize class I MHC and this recognition prevents the lysis of
the target cells (Bennett et al., 1995; Yokoyama et al., 1995).
Although NK cells have been primarily de®ned by their cytolytic activity,
they also perform many other functions. NK cells are potent producers of
cytokines such as TNF-a, IFN-g, granulocyte-macrophage colony-stimulating
factor (GM-CSF ), and IL-3 (Trinchieri, 1995). In vivo, NK cells play an im-
portant role in ®ghting infections by secretion of cytokines like IFN-g long be-
fore T-cell activation takes place and the T cells secrete their own cytokines.
IFN-g activates phagocytic cells for phagocytosis of microorganisms ( Dunn
and North, 1991). The induction of cytokine production by NK cells is medi-
ated by various nonspeci®c stimuli (immune complexes, target cells, micro-
organisms). Further, other cytokines produced by T cells and macrophages,
such as IL-2, IFN-g, TNF-a, IL-1, and IL-12, can also activate NK cells and
phagocytic cells and thus both cells play a central role in innate resistance to
certain microorganisms ( Fernandez et al., 1999). An important new cytokine,
IL-12, has been identi®ed and it is a potent stimulator of IFN-g secretion from
NK cells and B cells. Phagocytic cells, dendritic cells, and Langerhans cells are
major producers of IL-12 upon infection. Thus, IL-12 activates NK cells for
IFN-g secretion, and IFN-g then activates macrophages. IL-12 also acts on T
cells for enhanced generation of cytotoxic T lymphocytes (CTL). Further, NK
cells play a direct early role in IL-12-mediated induction of T-helper cells type 1
through secretion of IFN-g in antigen-speci®c adaptive immunity ( Trinchieri,
1995).
Although NK-cell activity can be regulated by the expression of inhibitory
and activating NKRs, NK cells can also become anergic or tolerant. For in-
stance, NK cells in class I-de®cient mice fail to reject autologous cells, and such
NK cells thus acquire a state of tolerance. Raulet et al. (1995) proposes that one
or more mechanisms might be involved in NK tolerance, namely: 1) speci®c
clonal elimination of potentially autoaggressive NK sets; 2) speci®c anergy of
the potentially autoaggressive NK set; and 3) potentially autoaggressive NK
cells might be altered to eliminate their autoaggression while retaining their
lytic potential. Jewett and Bonavida (1996) have demonstrated that NK cells
can undergo a stage of split anergy following their interaction with target cells:
a subset is programmed for cell death and another subset is functionally anergic
for cytotoxicity but can be activated for proliferation and cytokine production.
