Page 273 - Clinical Immunology_ Principles and Practice ( PDFDrive )

254 PART TwO Host Defense Mechanisms and Inflammation

Altered self
Missing self
NK cell

- - - -

Activating Inhibitory +++ +++
receptor receptor
Activating
MHC-I
Target ligand
cell

Inhibition Poor killing Killing Response determined
no killing by balance of signals
FIG 17.5 Natural Killer (NK)–Cell Recognition of Target Cells. NK cells express inhibitory
receptors for major histocompatibility complex (MHC) class I and activating receptors for a variety
of cellular, viral, and stress-induced ligands that alter the outcome of encounter with a target
cell. The missing-self hypothesis initially predicted that NK cells would be activated to kill in the
absence of MHC class I inhibition. However, an activating signal is also required. This activating
signal can be provided by cellular ligands or by viral or stress-induced proteins, termed “altered
self.” In the presence of both inhibitory and activating signals, the outcome is determined by
quantitative differences in signal strength between the two.

20
KEY CONCEPTS downstream signaling pathways and NK-cell effector functions.
Natural Killer (NK)-Cell Receptors In contrast, activating receptors use immunoreceptor tyrosine-
based activation motifs (ITAMs) to transduce stimulatory signals.
Inhibitory receptors: Engagement of an ITAM-containing receptor results in tyrosine
Recognize mostly major histocompatibility complex (MHC) class I phosphorylation and recruitment of adaptor molecules, including
ligands with high affinity FcεR1γ, CD3ζ, or DAP12/DAP10. The best-characterized activat-
Signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) ing receptor is CD16, an Fc receptor that binds IgG and is
Recruit phosphatases (SHP and SHIP) to prevent a cytotoxic response responsible for the antibody-dependent cellular cytotoxicity
Required for NK-cell licensing (ADCC) of human NK cells. CD16 recruits FcεR1γ and CD3ζ,
Activating receptors: which, in turn, attract the tyrosine kinases syk and ZAP70. These
Do not bind MHC class I molecules with high affinity
Ligands include viral molecules and stress-induced proteins molecules then promote effector functions via multiple signal-
Signal via immunoreceptor tyrosine-based activation motifs (ITAMs) transduction pathways.
Use several signaling adaptors, including DAP12
NK RECEPTORS THAT RECOGNIZE
MHC-I MOLECULES

molecules themselves, as predicted by the missing-self hypothesis, NK cells recognize a wide variety of MHC class I molecules of
there are many other classes of ligands. NK-cell receptors are both classic and nonconventional types. The receptors providing
classified into either activating or inhibitory types. This distinction this recognition fit broadly into the immunoglobulin-like and
was initially based on the in vitro properties of cross-linking lectin-like superfamilies. They show significant differences between
these receptors but is increasingly regarded as the expression of mice and humans.
the biochemical signal-transduction pathways activated by the
receptor. Interestingly, although this strategy of target recognition Killer Cell Immunoglobulin-Like Receptors in Humans
is conserved in all mammals tested, in rodents and humans, the The KIR genes are a family of 15 genes that are physically linked
21
receptors have evolved from two independent gene families, killer on chromosome 19. The locus shows a high degree of varia-
immunoglobulin-like receptors (KIRs) in humans and the Ly49 tion in humans, with both the number of KIR genes varying
family in mice (see Table 17.2). between individuals and extensive allelic polymorphisms. The
KIR family was originally called killer inhibitory receptors, but
NK-Cell Receptor Signaling subsequent studies have demonstrated that activating receptors
The signals derived from NK receptors are defined as inhibitory are also encoded by the KIR locus. As expected, the inhibitory
or activating in terms of their effect on NK-cell function. All KIRs contain the ITIM, whereas all activating KIR utilize DAP12
20
extensively characterized inhibitory receptors carry an immu- to transduce signals from an ITAM. Surface expression of KIR
noreceptor tyrosine-based inhibitory motif (ITIM) in their is acquired with maturation, driven by IL-15, and as such, NK
intracellular domain. Ligation of ITIM-containing receptors cells lacking KIR or NK cells with combinations of multiple
causes tyrosine phosphorylation and the recruitment of a variety activating and inhibitory KIRs can be found in human blood.
of phosphatases, including SHP and SHIP, that act to dampen Similar to most other NK-cell receptors, some T cells can