Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 328

for H-2D d , this recognition is weaker than for the inhibitory CD94/NKG2A
receptor [16] . NKG2D is a homodimer and does not associate with CD94 like
the other members of this family. NKG2D recognizes the nonclassical MHC
molecules: MICA and MICB and other non-MHC molecules, ULBP1, ULBP2,
and ULBP3, that are upregulated by a cell in times of stress, for example, in
virus-infected cells or tumor cells. In the mouse NKG2D ligands are retinoic
acid early inducible-1 (Rae-1), minor histocompatibility antigen H60, and
the murine UL16-binding protein-like transcript-1 (MULT-1) [9] .

Another family of immunoglobulin receptors, the leukocyte immunoglob-
ulin-like receptors (LILR), are also expressed by NK cells as well as other
immune cells [17] , and the genes encoding these receptors are in the LRC.
The LILRs deliver an inhibitory signal to NK cells. LILRB1 (LIR-1) expressed
on NK cells binds to an array of classical and nonclassical HLA class I mol-
ecules, including HLA-F and HLA-G. It has also been shown to bind to the
cytomegalovirus (CMV)-encoded glycoprotein UL-18 [18] .

The NCRs are a family of immunoglobulin-activating receptors and include
the receptors NKp30 and NKp44 in humans and NKp46 in both human and
mouse [19] . They have been shown to mediate NK cell cytotoxicity and lyse
tumor cells. NKp30 and NKp46 are constitutively expressed on both resting
and activated NK cells, whereas NKp44 is expressed only on activated NK
cells. Their ligands are varied. NKp30 recognizes the tumor ligand B7-H6;
the HLA-B-associated transcript 3 (BAT3), a nuclear protein released upon
heat shock treatment; and the CMV protein pp65. When NKp30 engages
with pp65 the NK cell is inhibited rather than activated, by dissociating
CD3ζ from NKp30 and preventing activation. NKp44 and NKp46 both rec-
ognize viral hemagglutinins [20,21] .

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Mouse and human NK cells also express other activating receptors. CD16,
a member of the Fc family of receptors, binds to the Fc portion of IgG anti-
bodies. Upon engagement CD16 mediates ADCC and lyses antibody-coated
targets. NK cells also express a variety of activating receptors that recognize
a wide range of diverse ligands [22] . DNAM-1 and CD96 have been shown
to bind to CD112 and CD155, both poliovirus receptors, and mediate cell
adhesion and increase NK cell killing. The glycoprotein CD160 interacts with
HLA-C, triggering NK cell cytotoxicity. NKp80, a C-type lectin-like receptor,
binds to AICL, which is expressed on myeloid cells and may be involved in
triggering NK cell lysis of acute myeloid leukemia (AML). Finally, CD2, a cell
adhesion molecule that binds to LFA-3, can act as a costimulatory molecule.
A final family of receptors expressed on a wide range of cells, including NK
cells, is the SLAM family of immunoglobulin-like receptors. NK cells express
CD244 (2B4), which binds to CD48; this interaction generally results in NK
cell activation but under certain conditions it can inhibit NK cell function
[23] . Other SLAM receptors include NTB-A and CRACC, which are their own
ligands, the interaction between them resulting in NK cell activation.

NK cell signaling

When an NK cell encounters a potential target, the NK cell must first
adhere to the target and form an immune synapse [24] . In the absence
of this adherence, NK cells are unable to lyse the cell. One example of an