Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 337

weak interaction between the inhibitory KIR and its cognate ligand. Indeed
studies looking at NK cell education and acquisition of function suggest
that inhibitory receptor interaction with its cognate ligand must reach a
particular threshold to gain function and that this threshold is much higher
for cytokine-producing functions than for cytotoxicity [37] . Also KIR2DL2
has been shown to be a stronger receptor for HLA-C than KIR2DL3 [75] and
may also interact with C2 HLA-C alleles. In pediatric transplant recipients,
KIR2DL2/3 + NK cells were poorly cytotoxic against leukemic blasts express-
ing C2 owing to KIR2DL2/3 being inhibited by C2 [76] .

Predicting NK cell alloreactivity is further compounded by the presence of
other inhibitory and activating receptors present on donor NK cells. The
inhibitory receptors NKG2A and LIR-1 may also suppress NK cell func-
tion following transplantation. HLA-E, the ligand for NKG2A, is expressed
on hematopoietic cells and could inhibit NK cell function even if there is a
KIR mismatch especially considering that reconstituting NK cells have high
NKG2A expression. Furthermore, while some tumors may downregulate
class I, HLA-E usually remains intact [77] . LIR-1, which binds an array of
class I alleles including HLA-G, should also be taken into consideration.

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Activating KIR may be involved in the GVL effect, as KIR2DS1-expressing
alloreactive NK clones have been shown to lyse targets expressing C2 and can
override NKG2A-mediated inhibition [78] . In the transplant setting, Pende
and colleagues [76] demonstrated KIR2DS1-mediated lysis of C2-homo-
zygous leukemic blasts and confirmed that NKG2A-inhibitory signaling
could be overcome. A large study of 1409 unrelated transplants examined
the roles of donor and recipient KIR haplotypes and found that transplants
from a KIR B haplotype donor resulted in lower relapse and improved sur-
vival for patients with AML [79] . The effect was not seen for patients with
ALL. As described earlier KIR A haplotypes consist predominantly of inhibi-
tory KIR and only one activating KIR, KIR2DS4. KIR B haplotypes, however,
have varying activating KIR gene content. To isolate which segment of the
haplotype may be involved in the protection effects observed, genes in the
KIR B haplotypes were divided into either centromeric or telomeric. Donors
with more centromeric KIR B haplotype (Cen-B) genes were associated with
the lowest level of relapse and highest overall survival. Donors were strati-
fied based on KIR B haplotype gene content into three groups: best (Cen-B
homozygous), better (more than two B-motifs without Cen-B/B), and neu-
tral donors (no or one B-motif ). It remains unclear why recipients who
receive a graft from a Cen-B-homozygous donor have preferable outcomes.

Even if donor-recipient pairs are carefully selected on the basis of predicted
NK alloreactivity and confirmation with in vitro lysing of recipient leukemic
blasts, the transplant environment also needs to be considered. NK cells are
the first lymphocyte to reconstitute following HSCT, and NK cell function
varies depending on the transplant source. Reconstituting NK cells have
differing receptor profiles than in the donor, which includes higher expres-
sion of NKG2A and altered KIR and NCR expression and lower than normal
overall function [80,81] . Therefore they can be considered developmen-
tally immature NK cells, and recovery of normal receptor repertoires and
function may take up to at least 1 year. Graft source also influences NK cell
recovery following HSCT. Cooley and colleagues [82] compared KIR receptor