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extracellular domain, a transmembrane domain, and a cytoplasmic
domain. The extensive allelic polymorphism observed in the Ly49 genes can
be explained by the different regions being encoded in unique exons of the
NK gene complex region in chromosome 6, which allows for multiple pos-
sible rearrangements, provides high receptor diversification, and accounts
for the many Ly49 receptors that have been identified
[9,10]
. Currently, 23
different Ly49 transcripts have been identified; among them, 13 Ly49 genes
are considered inhibitory receptors based on the presence of ITIMs in their
cytoplasmic domains (Ly49A, B, C, E, F, G, I, J, O, Q, S, T, and V) and 8 acti-
vating because of the lack of an ITIM (Ly49D, H, L, M, P, R, U, and W)
[10]
.
Within different mouse strains, Ly49 genes have shown high variability
[9]
.
Several studies have suggested that Ly49 receptors can interact with mul-
tiple H-2 alleles, though each may show a stronger affinity for a particular
H-2 allele
[11]
. Ly49A, for example, exhibits a broad MHC class I cross-
reactivity, but binds H-2D
d
with the highest affinity. In contrast, other
Ly49s, such as Ly49G2, show a more restrictive specificity for a particular
MHC class I allele. It is quite interesting that Ly49D, an activating receptor,
shares with the inhibitory Ly49A and Ly49G2 receptors affinity for H-2D
d
.
Ly49D reactivity against H-2D
d
has been demonstrated through cytotoxic-
ity assays
in vitro
and through its implication in H-2D
d
BM allograft rejec-
tion
in vivo
[12,13]
. Affinity of Ly49D for H-2D
d
may be lower than that
of Ly49G2 and Ly49A or may require costimulation or coreceptors for its
function
[9]
. Nevertheless, in H-2D
d
strains, the coexpression of self-spe-
cific inhibitory receptors was sufficient to allow self-tolerance of Ly49D
+
NK cells.
331
The frequency and amount of Ly49 expression in a particular NK cell seem
to be slightly influenced by H-2 expression in the host. However, because
of the distinctive mechanism of gene regulation that results in randomized
Ly49 expression, NK cells from a single host can express inhibitory recep-
tors that bind different H-2 alleles, and therefore there are NK cells with
inhibitory receptors able to recognize self-MHC and NK cells with inhibi-
tory receptors that do not. To explain how NK activation with such a dif-
ferential expression of Ly49s is regulated, a process known as NK licensing,
which is discussed later, has been proposed
[14]
.
Both humans and mice encode a family of C-type lectin-like receptors, known
as the CD94/NKG2 receptor family. They are disulfide-linked heterodimers
that are composed of an invariant common subunit, CD94. This is linked to
a glycoprotein encoded by a gene of the NKG2 family
[15]
. The NKG2 family
consists of four genes: NKG2A/B, NKG2C, NKG2E, and NKG2D/F (only in
humans). CD94/NKG2A is an inhibitory receptor that binds to the geneti-
cally invariant nonclassical MHC class I molecule—HLA-E in humans and
Q1-ab in mice. As the expression of HLA-E is promoted by binding of pep-
tides clipped from the leader sequence of classical HLA class I molecules,
it is thought that HLA-E expression acts as a barometer of classical class I
expression. The purpose of CD94/NKG2A may, therefore, be to monitor
class I expression in a quantitative way, whereas KIR receptors monitor each
allele individually. CD94/NKG2B appears to be a splice variant of NKG2A
and also binds HLA-E. CD94/NKG2C and NKG2D are activating recep-
tors. CD94/NKG2C also recognizes HLA-E, but, similar to Ly49D affinity
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