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(Doi 10.1002 - 9780470015902.a0000498.pub2) Teillaud, Jean-Luc - ELS - Antibody-Dependent Cellular Cytotoxicity (ADCC)
(Doi 10.1002 - 9780470015902.a0000498.pub2) Teillaud, Jean-Luc - ELS - Antibody-Dependent Cellular Cytotoxicity (ADCC)
. Mechanisms of Cytotoxicity
Jean-Luc Teillaud, Cordeliers Research Center, INSERM U.872, Université Paris-Descartes et
. Inhibition of Cytotoxicity
Université Pierre et Marie Curie, Paris, France
. Regulation of ADCC
Antibody-dependent cell-mediated cytotoxicity (ADCC) is ADCC is conferred by target-bound antibody and can be
the killing of an antibody-coated target cell by a cytotoxic induced in vitro by antibody concentrations well below
effector cell through a nonphagocytic process, charac- those needed to activate complement-mediated lysis.
terised by the release of the content of cytotoxic granules Receptors for the Fc region of Ig (FcR) on the plasma
or by the expression of cell death-inducing molecules.
membrane of the effector cell are necessary but not suf-
ficient for ADCC activity. Once antibody has bound to the
ADCC is triggered through interaction of target-bound
target cell, its interaction with either activating or inhibi-
antibodies (belonging to IgG or IgA or IgE classes) with tory FcR on the cytotoxic effector cell appears to dictate the
certain Fc receptors (FcRs), glycoproteins present on the precise signalling pathways that are stimulated. When
effector cell surface that bind the Fc region of immuno- target-bound antibodies crosslink activating FcR (char-
globulins (Ig). Effector cells that mediate ADCC include acterised by the presence of an immunoreceptor tyrosine-
natural killer (NK) cells, monocytes, macrophages, neu- based activating motif, ITAM, in their intracellular (IC)
trophils, eosinophils and dendritic cells. ADCC is a rapid domain or in the intracellular domain of the associated
effector mechanism whose efficacy is dependent on a transducing unit termed g chain), a cytotoxic pathway is
number of parameters (density and stability of the anti- initiated that results in the release of mediators such as
gen on the surface of the target cell; antibody affinity and perforin, granzymes, tumour necrosis factor (TNFa) and
reactive oxygen intermediates (ROI) – which induce target
FcR-binding affinity). ADCC involving human IgG1, the
cell death. Conversely, ligation of inhibitory FcR (char-
most used IgG subclass for therapeutic antibodies, is
acterised by the presence of an immunoreceptor tyrosine-
highly dependent on the glycosylation profile of its Fc based inhibitory motif (ITIM) in their IC domain) prevents
portion and on the polymorphism of Fcc receptors. effector cell activation, resulting in survival of the target
cell.
Introduction
Fc Receptors are Trigger Molecules
Antibody-dependent cell-mediated cytotoxicity (ADCC) for ADCC
was initially described by Moller in 1967 as the ability of
natural killer (NK) cells – at the time identified only as
As noted earlier, FcR on the surface of cytotoxic effector
lymphocytes – to destroy antibody-coated target cells. A
cells are required for ADCC (Fanger et al., 1989). Separate
nonphagocytic mechanism, whereby most leucocytes can
genes that are members of the immunoglobulin (Ig)
kill target cells in the absence of complement and without
supergene family encode different FcR: FcgR specifically
major histocompatibility complex (MHC) restriction (a
bind IgG, FcaR bind IgA, FceR bind IgE and Fcm/aR bind
mechanism by which specific cytotoxic T cells (CTLs) kill
both IgM and IgA (van Egmond et al., 2001a; Dombrowicz
target cells expressing peptides loaded onto surface MHC
et al., 2000; Kinet and Launay, 2000; Ravetch and Bolland,
Class I molecules) thus became apparent. The specificity of
2001; van der Poel et al., 2011). In humans, it is clear that
members of the following FcR classes are all capable, when
eLS subject area: Immunology crosslinked, of activating ADCC: FcgRI (CD64), FcgRIIa
and FcgRIIc (CD32), FcgRIIIa (CD16) (Figure 1), FcaR
How to cite: (CD89) and FceRI. In mouse, ADCC can be achieved
Teillaud, Jean-Luc (July 2012) Antibody-dependent Cellular
through the crosslinking of FcgRI, FcgRIII and FcgRIV as
Cytotoxicity (ADCC). In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0000498.pub2
there is no activating FcgRIIa (Nimmerjahn and Ravetch,
2008). In addition, it has also been shown that engagement
FcRI
FcRIIIA FcRIIA/C
(CD64)
(CD16) (CD32)
( or )
Figure 1 Schematic view of human-activating FcgR. In most cases, human-activating Fcg receptors comprise an IgG binding a chain associated with a
transducing subunit, a g chain (gg) homodimer. In NK cells, the presence of a g/z heterodimer or of a z/z homodimer has also been reported (the z chain is
also part of the T cell receptor (TcR) complex). The associated g or z chain contains an ITAM (immuno-receptor tyrosine-based activating motif) (black
square) that is phosphorylated upon crosslinking of FcgR. Human FcgRIIa is the only activating receptor where the IgG-binding a chain intracellular domain
contains an ITAM, although its association with a transducing g chain homodimer has been debated. Myeloid cells can express both activating and inhibitory
FcgRIIb (not shown in the diagram) and it is considered that cellular activation will result from the fine tuning of the balance between activating and
inhibitory signals. NK cells express activating FcgRIIIa, although the expression of activating FcgRIIc and of inhibitory FcgRIIb by small NK cell subsets has also
been reported. FcgRIIIa is also expressed by some T cells. FcgRIIIb, a GPI-linked surface receptor expressed by neutrophils is not presented. In mouse, there is
no FcgRIIa and inhibitory FcgRIIb is referred only as FcgRII. In contrast, there is another activating FcgR, termed FcgRIV, also associated with a g chain
homodimer.
of mouse inhibitory FcgRII leads to inhibition of ADCC et al., 2008), but whether these receptors impact NK cell-
activation (Clynes et al., 2000). The balance between acti- mediated ADCC mediated through FcgRIIIa in some
vating and inhibitory FcgR thus appears to be a crucial circumstances remains to be elucidated.
determinant of the magnitude of ADCC that is induced
when the effector cell engages the antibody-coated target Monocytes, macrophages and dendritic cells
and expresses both types of Fc receptors (Nimmerjahn and
Ravetch, 2008; Abes et al., 2009). See also: Antibodies; Monocytes and macrophages express all three classes of
Antibody Classes; Antibody Function; Fc Receptors; IgG receptors, FcgRI (CD64), FcgRII (CD32) and
Hypersensitivity: Antibody-mediated Cytotoxic (Type II) FcgRIII (CD16) (see Figure 1), as well as the receptor for
IgA (CD89) (Ravetch and Bolland, 2001; van Egmond
et al., 2001a; Nimmerjahn and Ravetch, 2008). Each has
been shown to be capable of triggering phagocytosis and
Cellular Effectors of ADCC ADCC by monocytes and macrophages. Although only
low levels of FcgRIIIa are expressed on freshly isolated
Natural killer cells monocytes, this receptor can be markedly increased when
monocytes mature into macrophages or are cultured with
NK cells are perhaps the most reliable effectors of ADCC activating cytokines such as interferon g (IFNg). Cytokine
when tested in cell culture cytotoxicity assays (Perussia, activation has also been shown to induce expression of
2000). When freshly isolated from circulating blood, a large FceRI. It has been noted that activated macrophages have
subset of human NK cells (defined as CD56dim CD16+) high FcgRIIIa/IIb ratios, favouring cell activation,
express relatively high levels of the type IIIa IgG receptor whereas quiescent effectors have low IIIa/IIb ratios, pro-
(FcgRIIIa or CD16a) and very efficiently mediate ADCC viding a high threshold for cell activation (Ravetch and
of tumour cells that are coated with antitumour IgG (Figure Lanier, 2000; Nimmerjahn and Ravetch, 2008). Human
2). NK cells appear not to express other classes of Fc blood dendritic cells also express IgG FcR and are potent
receptors and, therefore, are not activated for ADCC by effectors in antibody-dependent cellular cytotoxicity
IgA, IgE or IgM. FcgRIIIa is present on both NK cells and (Schmitz et al., 2002). In mouse, a critical role of FcgRIV in
macrophages as a transmembrane receptor that is associ- ADCC mediated by monocytes, macrophages and neu-
ated with the FcR g chain, an activating molecule involved trophils has been suggested using FcgRIV-deficient mice
in signal transduction. This association with the g chain (Nimmerjahn et al., 2010).
was found to be essential both for surface expression of
FcgRIIIa and for signal transduction following engage- Neutrophils and eosinophils
ment of this receptor by IgG. In contrast, FcgRIIIb
(CD16b) found on human neutrophils is expressed as a Freshly isolated neutrophils do not lyse tumour targets
phosphatidyl inositol glycan-linked receptor that does not through FcgR, but can be activated by granulocyte–
associate with the g chain and does not activate tumour cell macrophage colony-stimulating factor (GM-CSF) to
killing. Only FcgRIIIa, and not FcgRIIIb, is found in mice. mediate killing through FcgRIIa, and by IFNg to mediate
The expression of activating FcgRIIc and of inhibitory killing through FcgRI and FcgRIIa. The type of FcgRIII
FcgRIIb on small subsets of circulating NK cells has been expressed by human neutrophils (FcgRIIIb, a GPI-linked
reported (Metes et al., 1994; Sulica et al., 2001; Dutertre surface receptor) does not mediate cytotoxicity of tumour
granzyme B, may be involved in deoxyribonucleic acid requirement for active participation of the effector cell such
(DNA) fragmentation observed in target cells after as release of toxic mediators by the effector cell. This has
engaging a cytotoxic effector cell. However, studies using been shown with anti-CD20 antibodies whose binding to
granzyme B-deficient mice suggest a less important role for CD20 expressed by lymphoma cells triggers a significant
granzyme B in cytotoxicity. Molecular studies of patients apoptosis only when a FcgR-mediated crosslinking has
with inherited defects that impair cytotoxic functions have been achieved.
also helped to decipher the intimate mechanisms of cyto- In conclusion, multiple pathways may be involved in
toxicity by NK cells. Notably, it has been shown that the how an effector cell mediates ADCC of an antibody-
cytotoxic function requires the cooperation of the lysoso- opsonised target cell. These include perforin, cytolytic
mal cytotoxic granule and the endosomal exocytic vesicle. enzymes, reactive oxygen intermediates and apoptotic
A rapid polarisation of these two types of granules is signalling both with dependent and independent of Fas/
observed, followed by a coalescence near the cell–cell FasL interactions. Several mechanisms may combine to
contact area (Ménager et al., 2007). In vivo imaging mediate cytotoxicity depending on a variety of factors. The
experiments have shown that tumour cells form stable relative importance of each in vivo and ex vivo will continue
conjugates with macrophages and neutrophils expressing to be dissected using knockout mice and/or effector cells
FcgRs in tumour-bearing mice treated with a tumour- from individuals deficient in specific effector mechanisms.
specific antibody (Hubert et al., 2011). The contact zone Intra-vital imaging and in vitro imaging analyses should
accumulated actin, FcgR and phosphotyrosines. These in make it possible to better understand the in vivo dynamics
vivo ADCC synapses appear to be organised in multifocal of ADCC and the formation of the ADCC synapse.
supra-molecular activation clusters. Another mechanism
of target cell destruction is the engagement of Fas by Fas
ligand (FasL), molecules expressed, respectively, on the
surface of some target and effector cells. This interaction Inhibition of Cytotoxicity
initiates a cascade of signals in the target cell resulting in
apoptosis of the target. Crosslinking of FcgRIIIa on NK Fine tuning between activating and inhibitory pathways is
cells induces the expression of FasL, enabling them to kill now also understood to be a critical determinant of ADCC
Fas+ targets. Therefore, FasL/Fas interaction may be an activity (Billadeau and Leibson, 2002; Ravetch and Lanier,
important mechanism of ADCC mediated by NK cells. 2000; Nimmerjahn and Ravetch, 2008). FcgRIa (CD64),
Myeloid cells are able to destroy antibody-opsonised FcgRIIa (CD32) and FcgRIIIa (CD16a); FcaR (CD89)
targets by phagocytosis as well as by extracellular lysis. and FceRI are all capable of mediating ADCC when
Targets ingested phagocytically are destroyed in intracel- engaged by their respective ligands and crosslinked. Con-
lular phagolysosomes of the effector cell. The mech- versely, an inhibitory signal is generated upon crosslinking
anism(s) by which myeloid cells mediate extracellular lysis of FcgRIIb which contains cytoplasmic ITIM sequences,
of antibody-opsonised target cells has been controversial. aborting cellular activation through ITAM-containing
It is clearly different from ADCC mediated by NK cells. In receptors. The presence or absence of signalling through
one in vitro system, the mechanism of ADCC mediated by other immune inhibitory receptors on ADCC effector cells
myeloid cells has been shown to be distinct from that also influences cytotoxic activity. These receptors, with
mediated by NK cells based on divalent cation require- acronyms such as killer inhibitory receptor (KIR) (or
ments (Graziano et al., 1989). ADCC mediated by NK cells CD158), CD94/NKG2 (NKG2, an activating receptor
via FcgRIII was Ca2+ dependent and Mg2+ independent. for Natural Killer cells is also known as CD159a) and
In contrast, ADCC mediated by monocytes or by IFNg- immunoglobulin-like transcript (ILT) (also called leuco-
activated PMN via FcgRIa or FcgRIIa, or by peritoneal cyte inhibitory receptor (LIR or CD85)) associate with
macrophages via FcgRIa, FcgRIIa or FcgRIIIa was Mg2+ SHP-1 (Src homology region 2 domain-containing phos-
dependent and Ca2+ independent. Thus, even though phatase-1) and SHP-2 (Src homology region 2 domain-
macrophages and NK cells both mediate ADCC via containing phosphatase-2) phosphatases to inhibit cell
FcgRIIIa, the mechanism by which these two types of activation.
effector cells mediate their killing is distinct. Monocytes, The effect of FcgRIIb on ADCC and tumour growth
macrophages and neutrophils release ROI when FcR in vivo was demonstrated in FcgRIIb-deficient mice. Using
are crosslinked, and ROI have been implicated as the models of antibody-mediated tumour treatment, Clynes
mediators of target cell death. However, other mechanisms et al. (2000) demonstrated that FcgRIIb-deficient mice were
must also exist since neutrophils isolated from patients with able to inhibit tumour growth and protect from tumour
chronic granulomatous disease (CGD), whose cells lack metastasis as compared with wild-type mice. This finding
the ability to form ROI, were able to mediate ADCC as confirmed that FcgRIIb acted as an inhibitory receptor.
well as neutrophils isolated from normal donors (Roberts One interesting development of this observation has been
et al., 1993). Finally, it has been shown that when antibody the generation of antitumour IgG antibodies that weakly
binds to an apoptotic trigger molecule on the target bind the inhibitory FcgRIIb, whereas strongly engaging
cell, FcR crosslinking of the target-bound immunoglobulin activating receptors (Shields et al., 2001; Stavenhagen
can induce apoptotic cell death, apparently without a et al., 2007).
presence of phenylalanine makes FcgRIIIa a weaker include target cell apoptosis as well as effector cell release of
binder to human IgG1 as compared with FcgRIIIa har- toxic molecules such as perforin, granzyme B, TNFa,
bouring a valine. It has been demonstrated in vitro that NK reactive oxygen and reactive nitrogen.
cells derived from Val/Val homozygous donors exhibit a
stronger ADCC against IgG1-coated tumour cells as
compared with Phe/Phe donors. Interestingly, an associ-
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