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necrosis factor-α (TNF-α), transforming growth factor-β, macrophage
inflammatory protein-1β (MIP-1β), and RANTES, which can modulate the
adaptive immune system, recruit and stimulate other immune cells, and
stimulate or inhibit hematopoiesis. NK cells enhance the immune response
by eliminating virally infected or tumor cells through direct killing, medi-
ated by the release of perforin and granzyme, ADCC-mediated killing
through CD16, or the induction of apoptosis through Fas ligand (FasL).
NK cell receptors
Under normal homeostatic conditions, a balance of activating and inhibitory
signals tightly controls NK cell function (
Table 15.1
). The best-characterized
family of NK cell receptors in humans is the inhibitory killer-immunoglob-
ulin-like receptor (KIR) family. KIRs are type I transmembrane molecules
belonging to the immunoglobulin (Ig) superfamily
[5]
. Genes encoding
KIR are found on chromosome 19q13.4 in the leukocyte receptor complex
(LRC) and are classified according to their number of immunoglobulin-like
extracellular domains (two domains (2D) or three domains (3D)) and on
the length of their cytoplasmic tail (long (L) or short (S)). KIRs that possess
long cytoplasmic tails contain immunoreceptor tyrosine-based inhibi-
tory motifs (ITIMs) and thus are inhibitory receptors. KIRs that have short
cytoplasmic tails lack ITIMs, resulting in an activating function. Short-tail
KIRs associate with the adaptor molecule DAP-12, which has an immuno-
receptor tyrosine-based activation motif (ITAM) leading to cell activation
if the KIR binds to its ligand. When the inhibitory KIRs engage their ligand,
tyrosine kinase is phosphorylated, leading to the recruitment of SHP-1 or
SHP-2, which in turn dephosphorylates protein substrates associated with
activating receptors. KIR gene content differs between populations, but can
be divided into two broad haplotypes, KIR A and KIR B haplotypes. KIR A
haplotypes contain only one activating receptor, KIR2DS4, whereas KIR B
haplotypes are far more varied, consisting of two or more activating recep-
tors. Furthermore, KIR genes are highly polymorphic, with several alleles
described for each KIR gene.
329
Inhibitory KIRs recognize allelic epitopes present on certain human leu-
kocyte antigen (HLA) class I molecules. KIR2DL1, KIR2DL2, and KIR2DL3
recognize HLA-C alleles, with KIR2DL1 recognizing those with an Asn77
and Lys80 (HLA-C2) and KIR2DL2 and KIR2DL3 recognizing those with a
Ser77 and Asn80 (HLA-C1). KIR3DL1 recognizes HLA-A and HLA-B alleles
with the Bw4 motif. The ligands for KIR3DL2 remain controversial. HLA-
A3 and HLA-A11 have been implicated as possible ligands, but KIR3DL2
recognition may be peptide specific. KIR2DL4 is an unusual KIR receptor
as it expresses both an ITIM and an ITAM and has the capability of both
activating and suppressing NK cell function. Its ligand is thought to be
HLA-G.
Ligands for the activating KIRs have not been completely identified.
KIR2DS1 can recognize HLA-C2 alleles, similar to its inhibitory counterpart,
albeit with a much lower affinity
[6]
. Furthermore, KIR3DS1 has been linked
to human immunodeficiency virus (HIV) progression
[7]
and several other
activating KIRs have been linked to other infectious diseases
[8]
. However,
current data suggest that KIR3DS1 does not directly use Bw4 as its ligand.
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