1. Human natural killer cell deficiencies
Jordan S. Orange
Purpose of review Abbreviations
Human natural killer cell deficiencies are a relevant clinical ANKD absolute natural killer cell deficiency
entity that provides insight into the role of natural killer cells CMV cytomegalovirus
CNKD classical natural killer cell deficiency
in host defense, as well as the basic biology of natural killer EBV Epstein-Barr virus
cells. Since previously reviewing these disorders, FHL familial hematophagocytic lymphohistiocytosis
FNKD functional natural killer cell deficiency
significant developments warrant their reconsideration. HLH hematophagocytic lymphohistiocytosis
Recent findings HSV herpes simplex virus
NK natural killer
Human natural killer cell deficiencies can occur as part of a NKT cell natural killer T cell
more pervasive immunodeficiency syndrome or, rarely, in SCID severe combined immunodeficiency
VZV varicella zoster virus
isolation. The most informative examples of the former are in WAS Wiskott-Aldrich syndrome
the context of a known genetic defect, because the WASp Wiskott-Aldrich syndrome protein
deficiency of natural killer cell development or activity can
be attributed to the specific gene function. Since last ß 2006 Lippincott Williams & Wilkins
reviewed, there are five human gene mutations that are now 1528-4050
appreciated to affect natural killer cells, and additional new
insights into natural killer cell biology have been obtained
through seven others. Six new reports of isolated natural Introduction
killer cell deficiencies, as well as a suggested classification Natural killer (NK) cells are lymphocytes of the innate
scheme, are also reviewed. immune system that are capable of a number of useful
Summary and important functions (reviewed in [1]). They are
Appreciation of human genetic syndromes that include considered to be part of innate immunity because they
natural killer cell deficiencies, as well as new cases of do not rearrange their germline DNA to obtain speci-
isolated natural killer cell deficiencies, continue to advance ficity. As a result, they rely upon an array of receptors with
the understanding of natural killer cell biology and solidify distinct specificities that can activate NK cells to generate
the role of natural killer cells in defense against human function. These include receptors that can sense cell
herpesviral infection. stress or pathogen-specific signatures. The function of
Keywords
these activation systems is restrained by inhibitory recep-
cytotoxicity, herpesviruses, natural killer cell deficiency,
tors that, in the majority, recognize alleles of class-I
natural killer cells, natural killer T cells, primary
MHC. The coexistence of these two systems creates a
immunodeficiency
balance where NK cells can be readily activated by cells
that become distinguished from normal for a large num-
Curr Opin Allergy Clin Immunol 6:399–409. ß 2006 Lippincott Williams & Wilkins.
ber of reasons.
Department of Pediatrics, University of Pennsylvania School of Medicine, After a NK cell is activated by contact with a susceptible
Philadelphia, USA target cell, it is capable of several distinct functions.
Correspondence to Jordan S. Orange, The Joseph Stokes Jr Research Institute of Cytotoxicity is the best known, but cytokine production
the Children’s Hospital of Philadelphia, Division of Allergy and Immunology,
Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 and costimulation of other immune cells are also import-
Civic Center Blvd, ARC-1216F, Philadelphia, PA 19104, USA ant. The last two activities can be readily elicited by the
Tel: +1 267 426 2836; e-mail: orange@mail.med.upenn.edu
exposure to appropriate soluble signals in addition to cell
Current Opinion in Allergy and Clinical Immunology 2006, 6:399–409 contact. NK cell functions have been demonstrated to be
essential in the control of numerous infections and dis-
ease states, using animal models [2–4]. Their role in
human diseases is not as well established although there
is very strong supporting evidence in a number of con-
ditions. One critical demonstration of how NK cells
defend against disease and participate in human host
defense is derived from rare deficiencies of NK cells that
have been described. These include deficiencies of NK
cells that are part of a larger immunological syndrome,
but also isolated deficiencies of NK cells. A recurring
399

2. 400 Primary immune deficiency disease
theme of the human deficiencies of NK cells, which is Autoimmune lymphoproliferative syndrome with
also substantiated through in-vitro and animal-based immunodeficiency (caspase 8 deficiency)
experimental systems, is an important role for NK cells Caspase 8 deficiency results in a form of autoimmune
in defense against infectious disease caused by the her- lymphoproliferative syndrome (ALPS) that is associated
pesvirus family of viruses. with a combined immunodeficiency affecting numerous
cell types. The ALPS phenotype in caspase 8 deficiency
Since initially reviewing the human NK cell deficiencies results from an upstream requirement for caspase 8 in the
in 2002 [5], substantial progress has been made in the activation of caspase 3, which in turn is required for
recognition of additional patients affected by isolated NK apoptosis [6]. The immunodeficiency phenotype results
cell deficiencies. Additionally, progress has been made in from a requirement for caspase 8 in immunoreceptor-
understanding the impact of novel as well as previously induced NF-kB activation. Specifically, caspase 8 links
appreciated genetic immunodeficiencies upon NK cells. the complex consisting of CARMA1, BCL10 and
Through each of these efforts, further insight has been MALT1 to the inhibitor of NF-kB kinase complex
gained into the role of NK cells in protection against (IKK) [7]. NK cells derived from patients deficient in
human disease, as well as the basic biology of human NK caspase 8 have impaired activation receptor-induced
cells. This review does not comprehensively cover the stimulation and NF-kB nuclear translocation. The
impact of genetic immunodeficiencies upon NK cells, as requirement for the IKK complex for NK cell function
the majority of what was previously reviewed is has been previously demonstrated through studies of
unchanged and still valid. Instead, focus in this area will human IKK-g deficiency (NEMO deficiency) [8,9]. Cas-
be directed to data reported since the last review. In the pase 8-deficient patients are susceptible to infectious
case of the isolated NK cell deficiencies, a more com- disease indicative of their combined T cell and B cell
prehensive review is presented in light of several recently deficiency, such as upper respiratory bacterial infection
described cases. and even bronchiectasis [10]. These patients also experi-
ence mucocutaneous herpesviral disease, thus suggesting
New associations between genetic disease a potentially relevant NK cell deficit.
and natural killer cell deficiency
As the molecular understanding of deficiencies of host Familial erythrophagocytic lymphohistiocytosis type 3
susceptibility has increased, a number of previously (Munc 13-4 deficiency) and type 4 (syntaxin-11
unappreciated genetic etiologies have been discovered deficiency)
since the human NK cell deficiencies were last reviewed. Familial erythrophagocytic lymphohistiocytosis, also
In some cases, these gene mutations have been directly referred to as familial hematophagocytic lymphohistio-
linked to deficiencies of NK cells among other com- cytosis (FHL), represents a subset of patients with hema-
ponents of immunity. In other cases, some previously tophagocytic lymphohistiocytosis (HLH). HLH is a
appreciated genetic disorders of the immune system have phenotype that results from extraordinary immune acti-
only recently been linked to NK cell defects. These new vation typically following herpesviral infection, and it is
connections are summarized in Table 1 and are reviewed reviewed elsewhere [11]. In essence, an inability to medi-
here. This category represents an extension of the ate cytotoxic activity after infection prevents down-
‘known gene mutation in a disease that includes a NK modulation of immunity and/or eradication of infection
cell deficiency’ category from the previous review [5]. leading to a systemic inflammatory response syndrome.
Table 1 New associations between genetic defects and human natural killer cell deficiency
Gene Affected Natural killer
Disease mutated protein Infections cell defect Other defects Reference
Autoimmune CASP8 Caspase 8 Sinopulmonary Activation T cell, B cell [6,7]
lymphoproliferative bacterial receptor- activation defects.
syndrome with mucocutaneous induced TLR signaling
immunodeficiency herpesviruses stimulation defects
Familial erythrophagocytic UNC13D Unc-13 homolog Herpesviruses Cytotoxicity CTL defect [18,19]
lymphohistiocytosis-type 3 D (Munc13-4)
Familial erythrophagocytic STX11 Syntaxin-11 Herpesviruses Cytotoxicity CTL defect [16,17]
lymphohistiocytosis-type 4
Hermansky-Pudlak syndrome AP3B1 Adaptor-related Sinopulmonary Cytotoxicity CTL and neutrophil [21,22]
protein complex, bacterial defects
b1 subunit (AP-3) herpesviruses
Papillon-Lefevre syndrome CTSC Cathepsin C Periodontitis Cytotoxicity Neutrophil defects [24]
(herpesvirus)

3. Human natural killer cell deficiencies Orange 401
This phenotype is very similar to that found during the Munc13-4-deficient (and likely syntaxin-11-deficient)
herpesviral-induced accelerated phase of several other NK cells in that the lytic granules will fuse with the
well defined disorders of cytotoxicity, including Chekiak- cell membrane in the former. This can be measured
Higashi syndrome due to LYST mutation, Griscelli syn- experimentally by flow cytometry for CD107a, also
drome due to RAB27A mutation, and even X-linked known as LAMP-1 [19]. CD107a is contained in the
lymphoproliferative syndrome due to SH2D1A mutation lytic granules, but instead of being secreted is retained
(all reviewed previously [12]). As a group, these molecu- in the cell membrane after granule fusion. Thus, FHL2
lar diseases have helped to better define the cytolytic NK cells have normal expression of CD107a after acti-
process in human NK cells, which involves the vation, but FHL3 NK cells do not, as Munc13-4 is
intracellular traffic of lytic granules (a form of secretory required for the fusion process. Presumably, this
lysosome) containing the pore-forming molecule per- approach will also work for patients having mutations
forin, as well as granzymes and granulysins, to the of LYST and RAB27A, but these patients can also be
immunological synapse formed with a susceptible target distinguished by the albinism phenotype characteristic
cell [13]. The extrusion of these organelles through the of these mutations.
immunological synapse onto the target cell allows for its
controlled destruction. Hermansky-Pudlak syndrome (AP-3 deficiency)
Hermansky-Pudlak syndrome is closely related to Che-
There are currently three molecular defects that can kiak-Higashi and Griscelli syndrome in that patients also
result in familial causes of HLH. The first, FHL2, was have oculocutaneous albinism. They are distinguished in
defined in 1999 and results from mutation of the PFP1 that they have a bleeding diathesis, ceroid accumulation
gene encoding the pore-forming molecule perforin [14]. and, in some cases, immunodeficiency. There are two
The second (FHL3) and third (FHL4) are more recently known genes that cause Hermansky-Pudlak syndrome
defined. FHL3 is due to mutation of the UNC13 gene and the one that has been consistently associated with
encoding the Unc-13 homolog D protein, more com- immunodeficiency is caused by mutation of the ADTB3A
monly referred to as Munc13-4 [15], and FHL4 is due gene, encoding the b chain of the adaptor protein-3 (AP-
to mutation of the STX11 gene encoding the syntaxin-11 3) complex. This form of Hermansky-Pudlak is referred
protein [16,17]. Unlike some of the gene mutations that to as HPS2 and was initially appreciated as impairing
impair cytotoxicity to result in the HLH phenotype, cytotoxic T-cell lytic function. Specifically, AP-3-
Munc13-4 and syntaxin-11 play very late roles in the deficiency results in enlarged lytic granules that fail to
cytolytic process. In fact, the lytic granules in Munc13- move along microtubules to the immunological synapse
4-deficient cytotoxic cells traffic to the cell membrane and [20]. More recent studies have defined a similar defect in
dock, but fail to fuse [15]. Thus, Munc13-4 is essential in NK cells [21]. Interestingly, the NK cell cytolytic
priming the lytic granule for membrane fusion and, sub- defect persisted even after IL-2 stimulation, and was
sequently, exocytosis. Although detailed studies have not associated with a decreased cellular perforin content.
been performed in syntaxin-11-deficient human NK cells, As evidence of the significance of this defect and linkage
the deficit is likely to be very similar to that found in to other albinism/immunodeficiency overlap syndromes,
Munc13-4 deficiency. This is because syntaxin-11 is a an HPS2 patient having defective NK cell and cytotoxic
SNARE (soluble N-ethylmaleimide sensitive factor T-cell cytolytic activity has been reported to have HLH
attachment protein receptor) protein that functions to [22]. AP-3, therefore, can be viewed as a critical step in
facilitate lytic granule adherence to the inside surface of initiating granule traffic in human NK cells.
the NK cell membrane. There may ultimately prove to be
important differences, however, as clinical distinctions Papillon-Lefevre syndrome (cathepsin C deficiency)
have been described in FHL4 patients, including a later Papillon-Lefevre syndrome is characterized by hyperker-
age of disease onset and a relatively high incidence of atosis of the palms and soles and early onset periodontitis,
secondary hematologic malignancy [17]. which is in some cases believed to be viral in origin. The
disease is caused by mutations in the CTSC gene, which
Interestingly, NK cells in Munc13-4 are deficient in encodes cathepsin C (also known as dipeptidyl peptidase I).
their cytotoxic activity, but not uniformly so [18]. This Cathepsin C is a cysteine protease that acts in lytic
may be a feature of specific hypomorphic mutations or granules and other lysosomal organs to activate serine
redundancy in the granule-priming process, but is not proteases such as granzymes A and B. Deficiency of
consistent enough to discern FHL2 from FHL3, especi- cathepsin C was initially not found to lead to a cytolytic
ally because there are also genotype–phenotype defect in cultured NK cells [23], but it was later discovered
correlations among perforin mutations. Although that a defect was present in NK cells that had not been
specific data are not available, residual NK cell cytotox- activated in vitro [24]. Specifically, ex-vivo patient NK
icity has also been referred to in FHL4 patients [17]. cells contained reduced active granzyme B and increased
Perforin-deficient NK cells can be distinguished from amounts of pro-granzyme B. Incubation of patient NK cells

4. 402 Primary immune deficiency disease
with IL-2 restored their ability to process granzyme B and has not been previously associated with NEMO
mediate cytotoxicity. Thus, cathepsin C is a required deficiency. Similar to other NEMO-deficient patients,
component in readying the cytolytic effector molecules however, this patient had a defect in cytokine production,
required for NK cell activity. These observations also thus highlighting the specific contribution of deficient
highlight the powerful effects of IL-2 upon human NK cytotoxicity in the development of HLH. Unfortunately,
cells, as well as the need to study NK cells directly from the the exact role that NEMO plays in NK cell cytotoxicity is
patient without additional manipulation to fully appreciate still unknown, but is under investigation [26].
their attri-butes.
Familial erythrophagocytic lymphohistiocytosis type 2
New insights from additional study of (perforin deficiency)
diseases, which have been previously linked Increasing numbers of patients with HLH due to PFP1
to natural killer cell deficiencies gene mutations encoding the perforin protein have also
There have been several new important developments been recognized. Although the vast majority of these
for diseases whose link between a particular gene result in complete deficiency of the protein and a severe
mutation and NK cell deficiency has been previously clinical phenotype, there are some missense mutations
reviewed [5]. These new connections are highlighted in that lead to only partial reductions in cytotoxicity, and/
Table 2. Continued study of NK cells from patients with or presence of perforin protein [18,27,28,29]. Interest-
this category of diseases will provide deepening mechan- ingly, patients with these mutations tend to have HLH
istic insights into how human NK cells function. later in life and may have a milder clinical course. The
exact reasons why these altered perforin proteins lead to
NEMO deficiency less severe disease will likely provide insight into the
A number of patients with NEMO deficiency due to role of perforin in NK cell function, and the mechanism
mutation of the IKBKG gene have now been described as by which it facilitates target cell destruction. Presently,
having deficient NK cell cytotoxicity, as well as some it is appreciated that individual missense mutations can
clinical consequences that may be attributable to NK cell lead to incorrect perforin proteosomal processing,
defects [8,9]. A patient with this phenotype who also had increased degradation and/or incomplete maturation
HLH at 2 months of age has been reported [25]. This [29]. In addition, some missense mutations of the
particular child also had cytomegalovirus (CMV) retinitis perforin gene have also been identified in patients with
at 4 months of age. His NK cells possessed adequate hematologic malignancies [30,31], as well as in an adult
levels of perforin, but had cytotoxic activity that was with chronic active Epstein-Barr virus (EBV) infection
initially absent and persistently less than control. This [32]. These associations may point more specifically to a
case is especially informative in that the HLH phenotype requirement for NK cell cytotoxicity in hematologic
Table 2 New insights into natural killer cell biology and function from additional study of genetic diseases known to affect natural
killer cells
Disease Gene mutated Affected protein New insight Reference
NF-kB essential modulator IKBKG NEMO HLH phenotype [8,9]
deficiency
Familial erythrophagocytic PFP1 Perforin 1. Missense mutations can result in milder [18,27,28,29]
lymphohistiocytosis-type 2 phenotype; 2. missense mutations can
lead to aberrant perforin processing; 3.
mutations can be present in patients
with hematologic cancers without HLH
Severe combined IL2RG, JAK3 IL-2r gc, Janus Dispensability of IL-2, IL-4 and IL-7, but not [34–37]
immunodeficiency kinase 3 IL-15 signaling for natural killer cell
development
Bare lymphocyte syndrome TAP2 Transporter 1. CECAM can function as an alternative and [38,39,41]
associated with potent natural killer cell inhibitory receptor;
antigen processing 2 2. increased CCR2 function results in
abnormal natural killer cell accumulations
Wiskott-Aldrich syndrome WASP WASp 1. WASp-directed actin reorganization is [44–46]
required for integrin clustering at the natural
killer cell immunological synapse; 2. WASp is
required for cytotoxicity mediated by ex-vivo
natural killer cells; 3. IL-2 increases cytotoxicity in
WASp-deficient natural killer cells;
4. WASp can facilitate natural killer cell activation
by linking to NF-kB and NFAT activation

5. Human natural killer cell deficiencies Orange 403
tumor cell surveillance, and they are supported by syndrome resulting from deficiency of the transporter
transplantation data that define NK cells as possessing associated with antigen processing 2 (TAP-2). It has been
powerful graft-antitumor effects [33]. difficult to understand why NK cells from TAP-2-
deficient patients fail to lyse bystander host cells, as they
Severe combined immunodeficiency will have diminished MHC class I expression, thus pre-
Studies of the lymphocyte composition of patients with sumably making them highly susceptible to NK cell
severe combined immunodeficiency (SCID) have pro- cytotoxicity. Although earlier studies have helped
vided valuable insight into the requirements for human explain this phenomenon, a new line of evidence demon-
NK cell development. In particular, NK and T-cell strates that this does not occur due to increased expres-
negative SCID resulting from mutations of either the sion and function of the MHC class I-independent
IL2RG gene encoding the common gamma chain (gc) or inhibitory receptor carcinoembryonic antigen-related cell
the JAK3 gene encoding the Janus kinase 3 (JAK3) have adhesion molecule (CEACAM1) [38]. This increased
illustrated the need for cytokines using this signaling function correlated with decreased soluble levels of
pathway to generate NK cells. As both of these proteins CEACAM1, serving to augment the inhibitory effect
are required for the function of IL-2, 4, 7, 9, 15, and 21, mediated by cell surface CEACAM1 [39]. Another poten-
discerning exact cytokine requirements for NK cell tial explanation might derive from the recently appreci-
development has not been possible. Rare patients with ated phenomenon of NK cell licensing discovered in
SCID due to atypical IL2RG or JAK3 mutations, however, mice, wherein exposure to an MHC molecule is required
have been described as having NK cells. These to enable cytolytic potential in NK cells [40]. Even
mutations allow for selective cytokine signaling and thus though this does not translate perfectly, as TAP-2-
demonstrate specific NK cell developmental require- deficient NK cells can still mediate lysis of selected
ments. The first of these patients had an A156V substi- target cells, it is likely a contributing factor. In this light,
tution of gc and was unable to generate signals in impaired expression and function of the NK cell cyto-
response to IL-4 or IL-7, but maintained intact IL-2 toxicity receptor NKp46 on TAP-2-deficient patient
and IL-15 function [34]. The second patient had an cells point to a potential developmental defect [38].
IL2RG 468 þ3AC splice site mutation in intron 3 Further studies of TAP-2-deficient NK cells, however,
resulting in three distinct mRNA species [35]. These will provide additional human context for the NK cell
were the insertion of a stop codon, a twenty amino acid licensing hypothesis.
extracellular domain insertion due to the presence of a
cryptic splice site, and wild-type due to ‘leakiness’ of the Finally, a comprehensive proteomic analysis of NK cells
mutation. The patient had normal numbers of NK cells from TAP-2-deficient patients has helped to elucidate an
that could mediate cytotoxicity, but failed to proliferate unusual feature of the disease, which is the progressive
in response to IL-2. Although the exact mechanism was accumulation of NK cells in the skin and respiratory tract
not defined in this case, the results suggested the dis- [41]. This work demonstrated that patient NK cells had
pensability of IL-2 signaling relative to IL-15 signaling in increased expression and function of the CC chemokine
human NK cell development. A similar conclusion can be receptor 2 (CCR2), as well as increased serum and
derived from a patient having SCID due to predicted bronchoalveolar lavage fluid levels of CCR2 ligands.
G589S alteration in JAK3, who had a normal number of Although the mechanistic link between TAP-2
NK cells that could mediate some cytotoxicity against deficiency in promoting this abnormality is unclear, the
K562 target cells [36]. As IL-2 was unable to induce findings do explain the clinical phenotype and may high-
STAT5 phosphorylation in cells from this patient, the light an adverse consequence resulting from inappropri-
relative dispensability of IL-2 signaling for NK cell ate NK cell licensing.
development is highlighted and the importance of IL-
15 suggested. It is also worth mentioning a SCID patient Wiskott-Aldrich syndrome
who did not have an identifiable mutation, but had very Finally, significant advances have been made in under-
low T-cell counts and absent NK cells [37]. This case standing how the Wiskott-Aldrich syndrome (WAS)
occurred in a young boy and was especially interesting in protein (WASp) contributes to NK cell functions
that he had a specific deficit in expression and function of through additional study of NK cells from patients with
the IL-2/IL15Rb chain. Although the IL2RB gene and its the disease. The combined immunodeficiency WAS
1.1KB promotor regions had a normal sequence, the case results from mutations in the WASP gene that encodes
does further highlight an absolute requirement for IL-15 WASp, which is a cytoskeletal adaptor protein capable of
in human NK cell development. facilitating the branching of actin filaments. As WASp
can interact with at least 22 distinct proteins, its role in
Bare lymphocyte syndrome (TAP-2 deficiency) immunological function is likely to be complex [42].
Significant new understanding has also been gained into Furthermore, WASp is only one member in a family of
the NK cells found in patients with bare lymphocyte related proteins that can act to rearrange actin, and thus

6. 404 Primary immune deficiency disease
is likely to be redundant in some respects. In ex-vivo NK non-NK cell-dependent immune components should
cells that have been prepared directly from peripheral be largely normal. The first classification is Absolute
blood without any additional stimulation or activation, NK Cell Deficiency (ANKD) and it is defined by the
defective NK-cell function was appreciated [43]. This complete lack of NK cells and NKT cells. The inclusion
finding has been extended to a large cohort of WAS of both cell types in the ANKD diagnosis results from the
patients and correlates to some degree with the severity use of CD56, which is common to both NK cells and
of the particular disease-causing mutation [44]. Further- NKT cells, by flow cytometry to define NK cells. ANKD
more, the defect in cytotoxicity includes both natural is not defined as simply the absence of CD56, as NK cells
cytotoxicity and antibody-dependent cellular cytotox- and their functions must truly be absent from all tissues
icity (ADCC) [44]. These findings point to a critical role evaluated. The second classification is Classical NK Cell
for WASp in NK cell cytolytic functions. This is in large Deficiency (CNKD), which is the same as ANKD except
part due to inappropriate accumulation of filamentous that NKT cells are present. This includes invariant NKT
actin at the contact formed between the NK cell and cells (iNKT), which express CD3, CD56 and a limited
target cell (also known as the NK cell immunological repertoire of T-cell receptor genes, typically including
synapse) in WASp-deficient NK cells [43]. The WASp- Va24 and Vb11, that enable them to recognize glycolipid
directed F-actin reorganization was additionally shown antigen in the context of the non-classical MHC mol-
to be required for CD2 and integrin clustering at, and ecule CD1d. The third classification is Functional NK
polarization of perforin-containing lytic granules to the Cell Deficiency (FNKD), characterized by the presence
immunological synapse [45]. Furthermore, an initial of NK cells that have some significant and static abnormal
description [43] and subsequent in-depth investigation activity. This is most typically a defect in cytotoxicity,
[44] demonstrated that exposure of NK cells to IL-2 in but can include any combination of other functions
culture was able to overcome the functional NK cell such as specific activation receptor-induced cytotoxicity,
defect resulting from WASp deficiency. Given that a e.g. ADCC, cytokine production, target cell recognition
major susceptibility of WAS patients is to herpesviruses, range, adhesion, chemotaxis, and/or costimulation
IL-2 therefore may have therapeutic potential in WAS. capacity.
Culture-activated WAS NK cells are not entirely normal,
however. Even though many functions are returned, One controversy that exists in this group of disorders is
there is still a defect in the activation of NF-kB and whether they are inborn or acquired. Even though, to be
NFAT [46], demonstrating that WASp has important considered, the defect must be consistent over time, it is
functions other than just actin remodeling in NK cells. possible that some cases are the result of acquired but
immutable defects in NK cells. There is, however, one
Advances in the understanding of isolated identified gene defect that results in FNKD, and also
natural killer cell deficiencies several familial cases of ANKD have been reported. As a
Although the genetic defects affecting immunity are result, NK cell deficiency is now listed in the Online
useful in addressing questions of NK cell biology, the Mendelian Inheritance in Man database (entry 609981).
most important illustrations of the role of NK cells in
human host defense remain the rare isolated deficiencies Table 3 Classification of the isolated natural killer cell
of NK cells. These cases are essential in that they truly deficiencies
highlight the specific contributions that NK cells make in Diagnosisa Natural killer Natural killer Natural killer
cell functionb T cellsc cellsd
defense against disease and in the maintenance of health.
Determination of genetic lesions resulting in these phe- ANKD Absent Absent Absent
notypes will also provide great insight into the specific CNKD Absent Present Absent
requirements for NK cell development, survival and
FNKD Deficient Present Presente
function in a human context. Since last reviewed, there
has been important progress made regarding patients ANKD, absolute natural killer cell deficiency; CNKD, classical natural
killer cell deficiency; FNKD, functional natural killer cell deficiency.
with this diagnosis and illustrative new cases have been a
In natural killer cell deficiency, the observed defect must be consistent
reported. Unfortunately, specific new genes resulting in over time and non-natural killer cell immune components or non-natural
these phenotypes have still not been identified. Here, killer cell-dependent immune components should be normal.
b
Natural killer cell function as typically defined by cytotoxicity, but can
new cases of isolated NK cell deficiency are reviewed and include any function that can be attributed to natural killer cells. As many
considered in the context of previously reported cases. of these functions are also performed by other cells, it is important that
the deficit be specifically attributed to the natural killer cell.
c
Natural killer T cells as defined by the presence of CD3þ, CD56þ cells.
As proposed and described previously [1,5,12,47], the This includes the iNKT cell population expressing the Va24 and Vb11
classification of the isolated NK cell deficiencies can combination of TCR genes.
be facilitated by the division of these disorders into three
d
Natural killer cells as defined by, but not limited to CD3À, CD56þ cells.
e
Although natural killer cells by definition are present in FNKD, there may
categories (Table 3). In each of these, immunological be phenotypic abnormalities or absence of particular natural killer cell
assessments of non-NK cell immune components or subsets.

7. Human natural killer cell deficiencies Orange 405
The issue of immutability of the NK cell defect over time reports of this deficiency (Table 4). Two cases of ANKD
is an important aspect of the isolated NK cell were highlighted in the previous review of NK cell
deficiencies. This is especially relevant as many of the deficiencies [5]. One of these was the often-cited case
evaluations of NK cells performed to raise the suspicion of an adolescent female who had disseminated life-threa-
of a diagnosis are functional assays, and exogenous factors tening VZV followed by CMV pneumonitis and herpes
can reduce the number of NK cells in peripheral blood, simplex virus (HSV) [52]. This patient’s herpesviral
the function of NK cells in peripheral blood, or both. infections occurred over several years and required
These factors include a number of pharmaceutical agents life-long prophylaxis. She persistently lacked CD56þ
and psychosocial stress [48,49]. It is now also appreciated NK cells and NK cell cytotoxicity over an observation
that in some patients who have experienced severe period of over 6 years. The second older case was in an
varicella zoster virus (VZV) infection, a transient adolescent boy who had disseminated mycobacterium
deficiency of NK cells can also be observed [50]. This avium and then died of disseminated VZV infection
last report presents specific diagnostic challenges as VZV [53]. He lacked NK cells and NK cell function, but also
has been a significant factor in several patients who have had a number of other immunologic features that might
had consistent and not transient NK cell deficiencies. suggest a broader immunologic syndrome. His infectious
The reported transient deficiency, however, was very susceptibility, however, at least partially overlapped with
transient as NK cell function reappeared in all patients that of the initial patient and thus is useful.
by 4–6 weeks after initial appearance of the viral
exanthem. Overall, these findings highlight a need to Since the previous review, there have been four additional
perform repeated assessments of an individual patient’s reports that are important to discuss. It is not clear in all
NK cells and to consider exogenous factors. cases that NKT cells were also affected as they were not
specifically evaluated, but they are discussed collectively
Furthermore, the distinction between ANKD and in this section, as opposed to the next section, to allow
CNKD is an important one. In particular, the expanding comparison. The first was reported in two sisters, the oldest
number of functions attributed to NKT cells makes this of whom died at 18 months of age from disseminated CMV
essential. As an example, an isolated human deficiency of infection [54]. The younger sister has not experienced
NKT cells has been reported and has an impressive severe infectious disease, but has not been infected with
phenotype [51]. This child had disseminated vaccine herpesviruses. The older sister did not have CD2þ/CD3À
strain VZV despite having normal NK cell cytotoxicity lymphocytes and was assumed not to have NK cells. The
and an intact VZV-specific CD8þT cell response. younger sister did not have CD56þ/CD3À NK cells at birth
Although this highlights a potential and important role to 3 years of age and had negligible percentages of NKT
of NKT cells in defense against VZV, it underscores the cells. NK cell cytotoxicity was unmeasurable among
importance of defining the relative contributions of NK PBMC preparations. Both girls did have low CD8þ T cells
cells versus NKT cells to host defense. Thus, as the role at birth, as well as persistent neutropenia. The remainder
and importance of NKT cells have expanded signifi- of their immunity, however, appeared intact. Interestingly,
cantly it is very important to consider NKT cells and to by age 5, the surviving child’s NK cell percentages had
distinguish ANKD from CNKD. risen, approaching the 5th percentile for age, but with an
unusual preponderance of CD56þ/CD16À NK cells.
Absolute natural killer cell deficiency These sisters also had intrauterine growth retardation,
ANKD is defined as the complete absence of NK and facial abnormalities and eczema, suggestive of an over-
NKT cells and there have been at least six separate arching genetic syndrome. Some mechanistic insight into
Table 4 Reports of isolated absolute natural killer cell deficiency
Author Infection Outcome Associated abnormalities Reference
Biron VZV, CMV, HSV Died, bone marrow transplantation Low absolute lymphocyte counts [52]
age 21 years
Wendland VZV, M. avium Died M. avium age 19 years Low absolute lymphocyte and [53]
neutrophil counts. Decreased
antigen presenting cell function
Bernard A. CMV; B. none A. Died CMV age 18 months; B. living Low absolute neutrophil and [54]
CD8þ T cell counts
Etzioni VZV Died VZV age 29 months None [56]
Notarangelo VZV Successful HSCT age 4.5 years Neutropenia, lymphopenia [57]
Eidenschenk A. None; B. viral A. Alive; B. alive; None [58]
pneumonia; C. EBV; C. lymphoproliferation; D. alive
D. viral pneumonia

8. 406 Primary immune deficiency disease
the defect in this family has been reported in subsequent maximum LOD score of 4.51. This region contains 59
studies by the authors. Using T cells from the surviving genes, including the PRKDC gene encoding protein
patient, they have found impaired responses to IL-2 or IL- kinase, DNA-activated, catalytic polypeptide, which
15, as well as excessive spontaneous apoptosis, suggesting does give rise to an immunologic phenotype when
that IL-15-dependent NK cell survival may be specifically deleted in mice. Other interesting proteins encoded by
defective in this particular disorder [55]. genes in this region include the CAAT enhancer binding
protein delta, which is an important transcriptional reg-
The second new case of ANKD occurred in a 23-month- ulator and can be mutated in certain cancer cells. Further
old girl born to consanguineous parents, who had dis- studies of this family will likely provide a genetic etiology
seminated VZV infection with encephalitis [56]. She of ANKD, as well as valuable information regarding NK
had a recurrence of the VZV infection 6 months later, cell development and function.
which proved fatal. She did generate VZV-specific IgG,
had quantitatively normal T cell populations, and normal Classical natural killer cell deficiency
proliferative responses to T cell and B cell mitogens CNKD is defined as the absence of NK cells, but not
(including IL-15), but had drastically reduced numbers NKT cells. There have been no new cases reported since
of NK cells. She also had essentially absent NK cell the last review, but as mentioned, this could be affected
cytotoxicity, which could not be induced with IL-2. by the fact that NKT cells were not characterized in some
Although substantial longitudinal evaluations were not cases of ANKD. Two patients with CNKD have been
performed, this case is important in that the remainder of previously reported (Table 5); one had severe and recur-
her immunity was intact. Also, the consanguinity in the rent infection with Human Papilloma virus (HPV), and
family raised the possibility of a recessive genetic lesion. the other with fungi. Continued attention should be paid
to this category as studies of these patients have the
The third new report was associated with a more signifi- potential to provide great insight into the specific role of
cant overall immunological phenotype, but described a NK cells in host defense, as well as factors specific to NK
girl with total absence of CD16þ lymphocytes and NK cell development, survival, or both.
cell cytotoxicity who had disseminated VZV infection at
age 4.8 years [57]. She also had leukopenia, low B cells, Functional natural killer cell deficiency
and poor lymphocyte proliferative responses, and was FNKD is defined as the presence of normal numbers of
successfully treated with hematopoietic stem cell trans- NK cells that have some deficiency in their function in
plantation. Although her relatively late age at presen- the absence of other substantial immunologic abnormal-
tation distinguishes her from children with SCID, she ities. Due to the fact that NK cells are present in these
does appear to have some similarity to the NK cell patients, as determined using standard clinical flow cyto-
predominant SCID described in the section on SCID metric analyses, the diagnoses are difficult and require a
[37]. high degree of suspicion. Despite this challenge, there
are a number of important examples of patients with
The final new report of ANKD described four children abnormal host defense and isolated functional defects in
from three sets of consanguineous parents all from the NK cells. This diagnostic category is also most likely to
same family of Irish nomadic descent [58]. One child grow as subtleties of host defense are increasingly
had an EBV-related lymphoproliferation and two others related back to immunological phenotypes. The FNKD
had recurrent respiratory tract infections presumed to be category is also very valuable for understanding the
of viral origin. Each of these children (three male, one relative importance of specific NK cell attributes and
female) had low NK cell numbers. NK cell cytotoxic characteristics.
function, as well as IL-2-induced cytotoxicity, was absent
in the one patient tested. The specific phenotypic evalu- Previously, several reports of FNKD were reviewed [5]
ation of iNKT cells in two of the children also demon- and there have been two new reports worthy of mention
strated very low numbers of these cells. It is important to since that time (Table 6). The previously reviewed
point out that NK cells were low but not completely
absent from the affected members of this family. Table 5 Reports of isolated classical natural killer cell
Although, when tested, the function of the NK cells deficiency
was absent among total PBMC, it is unclear how the Associated
few existing NK cells functioned. It is also unclear if the Author Infection Outcome abnormalities Reference
phenotype of the few existing NK cells was normal. To Ballas HPV Died early 30s of HPV- None [69]
take advantage of the size and genetic similarity of this associated malignancy.
kindred, a genomic scan of the family was performed and Sister died of leukemia
in childhood
defined a 12 megabase linkage region on chromosome 8
(8p11.23-q11.21) that linked to the phenotype with a Akiba Fungi Fungal dissemination Lupus [70]

9. Human natural killer cell deficiencies Orange 407
Table 6 Reports of isolated functional natural killer cell deficiency
Author Infection Outcome Associated abnormalities Reference
Fleisher (A) EBV, progressive (A) Acutely fatal None [61]
(B) EBV, progressive (B) Died bronchiectasis
age 38
(C) EBV, progressive (C) Alive with recurrent
respiratory infection
Komiyama (A) Respiratory viruses Lymphoma None [62,71]
(B) Respiratory viruses
Aoukaty EBV ? Decreased LAIR-1 expression [63]
Gazit CMV, VZV Alive Uniform KIR2DL1 expression [67]
and absolute inhibition
De Vries EBV, HSV, VZV, ? FCGR3A 48H/H [60]
respiratory viruses
Jawahar HSV, respiratory viruses Alive FCGR3A 48H/H [59]
reports include the single known genetic cause of FNKD, overlap with the unusual occurrence of direct NK cell
which results from a homozygous mutation in FCGR3A infection with EBV and subsequent lymphoproliferation
gene, which encodes FcgRIIIA (or CD16) [59,60]. [64]. Individuals affected by this latter condition are
Although this gene is polymorphic, this rare variant described to have hypersensitivity to mosquitoes and are
results in a NK cell cytotoxicity defect and is associated more commonly Japanese, and the mechanism under-
with severe herpesvirus infections. Fortunately, the lying the disorder is unclear. Both of these diagnoses are
resulting CD16 variant molecule can be distinguished distinct from ‘chronic fatigue syndrome’, which has
from wild-type receptor using two different commercially been associated with EBV infection by some authors,
available monoclonal anti-CD16 antibodies B73.1 and and can perhaps be associated with transient and mild
3G8, the variant receptor not being recognized by the effects upon the NK cell population [65,66].
former. No new cases of this variety of FNKD have been
reported since initially reviewed. The second case is that of a 7-year-old child with severe
disseminated CMV and CMV pneumonitis, who later had
Additional work has also been performed in one of the severe VZV infection. The patient was assessed as having
other previously reviewed cases of FNKD [61] and has intact immunity, including NK cell cytotoxicity. NK cell
demonstrated a functional defect that has persisted for phenotype was also normal with the exception of uniform
over 20 years (LaRosa and Orange, in preparation). Inter- high-level expression of the inhibitory receptor KIR2DL1
estingly, this patient had an abnormal hardwired NK cell [67]. This was of functional significance as the patient’s
phenotype, suggesting there was an inherent defect in NK cells were completely inhibited by target cells expres-
NK cell activation or development. Since this functional sing HLA-Cw4 (a cognate ligand for KIR2DL1). The
defect occurred in three of four siblings within a single factors governing this unusual expression of a single
family (two of whom died prematurely – one from EBV KIR gene are uncertain, but the resulting potential for
and the other from repeated respiratory tract infections), broader inhibition of NK cells through consistent
it is likely to have been genetic in origin. The other KIR2DL1 function may provide a selective advantage
previously reviewed case also occurred in siblings, further to pathogens whose control typically depends upon NK
highlighting a potentially genetic etiology [62]. cell mediated defense. Since linking specific KIR haplo-
types to disease phenotypes has proven highly relevant
The two cases reported since the last review both [68], this case suggests that considering the specific expres-
involve phenotypic aberrations of NK cells that may sion levels of individual KIR is also important.
have functional consequences. The first was described
in a patient with severe EBV infection described as Conclusion
chronic and active [63]. This patient had decreased There are an increasing number of deficits in human NK
NK cell cytotoxicity among culture propagated NK cells cells that have either been attributed to a mechanism
but, interestingly, had very low expression of leukocyte- underlying a broader immunological syndrome, or that
associated immunoglobulin-like receptor 1 (LAIR1). represent isolated deficiencies within the NK cell popu-
The significance of this association is unclear, but is lation itself. The former group has continued to provide
interesting given the role of inhibitory receptor signaling insight into the specific functional and genetic require-
in NK cell licensing. In this light, it is worth mentioning ments of human NK cells. The latter group has further
the literature referring to chronic and active infections highlighted the role of NK cells in human host defense.
with EBV. This diagnostic entity is difficult and may Additional studies of both groups of NK cell deficiencies

10. 408 Primary immune deficiency disease
20 Clark RH, Stinchcombe JC, Day A, et al. Adaptor protein 3-dependent
will provide important insights into NK cell biology and microtubule-mediated movement of lytic granules to the immunological
their role in human health and disease. synapse. Nat Immunol 2003; 4:1111–1120.
21 Fontana S, Parolini S, Vermi W, et al. Innate immunity defects in Hermansky-
Acknowledgements Pudlak type 2 syndrome. Blood 2006; 107:4857–4864.
Demonstration that AP-3 is required for the normal formation and traffic of lytic
This work was supported by NIH grant AI055602, a subcontract from granules in NK cells.
the US immunodeficiency network, and a faculty development award
from the Education Research Trust of the American Academy of Allergy 22 Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistio-
cytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108:81–87.
and Immunology.
Report of the HLH phenotype in HPS2 demonstrating the importance of the
cytolytic defect resulting from AP-3 deficiency.
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