Red in Translation
Immune Responses in Cystic Fibrosis
Are They Intrinsically Defective?
Dmitry Ratner1and Christian Mueller1
1Pediatrics and Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts
Cystic fibrosis (CF), the most common lethal single-gene disorder
affecting Northern Europeans and North Americans, is caused by
mutations in the cystic fibrosis transmembrane conductance regu-
lator(CFTR)gene.Cftris achloridechannelandaregulatorof other
ion channels, and many aspects of the CF phenotype are directly
related to ion channel abnormalities attributable to CFTR mutation.
Lung disease is the most common limitation to the quantity and
quality of life for patients with CF. One aspect that continues to be
responses to certain pathogens. Altered responses to Pseudomonas
latter, are common in CF. Several lines of evidence suggest that the
ated in CF. A literature search reveals that, although the abnormal-
ities in CF immune cells have been recognized since the 1970s, few
studies until recently have appreciated the role that CFTR plays in
these cell types. A growing body of evidence has emerged that
points to neutrophils, macrophages, and T cells as being central to
of CF mortality. Primary CFTR defects in T cells are providing new
insights into the misorchestration of the CF immune system due to
aberrant signaling pathways. Defective CFTR function disrupts the
known to drive gene expression pathways. New evidence links this
hypothesis to anomalies in immune activation observed across
CF cell types, which could shed light on the inability of individuals
with CF to effectively clear pathogens. This review focuses on the
emerging role of Cftr in gene expression and other functions
in cells of the innate and adaptive immune system.
Keywords: cystic fibrosis; T cells; calcium; macrophages; allergy
Cystic fibrosis (CF) is the most common fatal single-gene dis-
order in North Caucasians, affecting approximately 30,000 chil-
dren and adults in the United States. CF is caused by mutations
in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene, which is an ATP-driven chloride channel in
thecellmembrane.CF hasvariablypenetrantpathology in mul-
tiple organ systems, but the respiratory system accounts for the
vast majority of morbidity and mortality. Patients with CF de-
velop chronic infections by opportunistic bacteria such as
Pseudomonas aeruginosa, Staphylococcus aureus, Haemophi-
lus influenzae, and Burkholderia cepacia (but not the more
commonly occurring Streptococcus pneumonia) at a greater
incidence than the general population. Infection is accompanied
by exaggerated inflammation with migration of large numbers
of neutrophils to the lungs. Pulmonary infection by P. aerugi-
nosa is usually the terminal complication in CF, with high mor-
Until recently, the main focus on CF pathology has been the
function of the Cftr channel in epithelial cells, with its malfunc-
tion leading to subsequent air–liquid interface dehydration in
the airways, thick mucus deposition, and impaired mucociliary
clearance. This phenomenon is hypothesized to allow bacterial
trapping, resulting in chronic lung infections. Although this is
responsible for much of the morbidity in CF, the intrinsic
effects of mutant CFTR on the immune system may exacer-
bate the pathology by promoting allergic reactions and hinder-
ing the proper clearance of pathogens in the CF lung.
In the last decade, an increasing number of investigators have
ticularly in the NFAT (1–3) and MAPK/ERK signaling path-
ways (4). These pathways are responsible for the transcription
of inflammatory mediators and many critical cellular processes
whose disruption could cause a plethora of possible pathologies.
These molecular findings resonate with observations that patients
with CF have a unique profile of proinflammatory cytokines even
in the absence of infection (5), together with a tendency toward
asthma (6–8), dermatitis (9), and allergic reactions (10–14). Of
particular concern is the high frequency of adverse drug reactions
among patients with CF because antibiotic treatment is critical
for their longevity.
Although most of these CFTR-related signaling abnormal-
ities are being studied in the context of hyperinflammation of
airway epithelial cells (AECs), they also play a major role in the
in the orchestration of inflammatory responses by the immune
system. These pathways have largely been described and dis-
covered in immune cells. This has led several groups to question
whether a primary CFTR-mediated defect in granulocyte,
monocyte, and lymphocyte lineages may contribute to the in-
fectious pathology in CF. Although the relative contribution
of compromised immunity and lung epithelium to CF mortality
must be clarified, new insights regarding this crucial question
are bringing it to the forefront and may have significant impli-
cationsforthedevelopment ofeffectivetreatmentstrategies for
CF. This review focuses on the new insights and disease models
that have emerged from these studies in CF immunology.
CFTR IN AIRWAY EPITHELIAL CELLS
One puzzling feature of CF is excessive inflammation inthe lungs.
Large numbers of neutrophils are present in the lungs of adults
and children with CF even in the absence of pathogens (5, 15),
where they cause proteolytic degradation of elastin and destruc-
tion of lung architecture (16). Is the excessive neutrophil activity
due to abnormal AEC secretion of neutrophil chemoattractants,
(Received in original form November 18, 2011 and in final form March 6, 2012)
Correspondence and requests for reprints should be addressed to Christian
Mueller, Ph.D., 381 Plantation Street, Suite 250, Worcester MA 01605. E-mail:
Am J Respir Cell Mol Biol
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1165/rcmb.2011-0399RT on March 8, 2012
Internet address: www.atsjournals.org
Vol 46, Iss. 6, pp 715–722, Jun 2012
or is it due to an intrinsic neutrophil defect? It appears that it
may be both, as we review in this section.
The etiology of CF lung inflammation in the field has been
a topic of debate. Some studies have found no difference in cyto-
kine secretion between CF and non-CF cells and have questioned
whether CF lung inflammation is caused by an intrinsic CFTR
defect (17–19). These studies have been primarily conducted in
epithelial cells, which may have left critical interactions with im-
mune cells unanalyzed. In fact, the negative results drawn by stud-
ies in cultured epithelial cells could be interpreted to suggest that
an intrinsic CFTR defect in immune cells, not AECs, may be the
source of CF lung inflammation. In vitro studies are conducted in
an artificial environment, and immune cells are notorious for be-
having differently in vitro than in vivo. Therefore, conclusions from
in vitro immunological studies must be analyzed with caution.
Interpretation of lung inflammation from in vivo studies can be
difficult because popular Pseudomonas delivery methods involve
inoculation of the lungs with Pseudomonas-laden alginate beads,
and these can elicit inflammation by themselves even in wild-type
controls or create chronic infection that even wild-type mice
cannot clear (20–22). Newer, optimized models have made
such studies more feasible and show that an intrinsic CFTR
defect is responsible for excessive lung inflammation and for
the inability to clear P. aeruginosa in mice (23, 24). It is not
clear whether these conclusions would hold true in humans
because these models use a nonmucoid strain of P. aeruginosa,
whereas clinical isolates from patients with CF are typically
biofilm-forming strains. Moreover, expression of CFTR and
other Cl2channels may differ between mice and humans,
which can further confound the translatability of such studies.
AECs play a significant role in the infectious pathology of CF
and represent an interface between pathogens and the immune
system. Thus, the intrinsic changes in Cftr-deficient AECs are
important not only in how they affect interaction with pathogens
but also in how they affect communication with immune cells.
Several groups have described up-regulation of signaling path-
ways associated with proinflammatory cytokine transcription
in CF epithelial cells (25–30). In particular, Cftr-deficient AECs
that have been exposed to P. aeruginosa demonstrate increased
activation of the proinflammatory transcription factor nuclear
factor-kB (NF-kB), which subsequently drives the increased
expression of IL-8 (1, 2). IL-8 is a potent neutrophil chemo-
attractant, and its overexpression by AECs could partly ex-
plain the pulmonary hyperinflammation seen in CF. CF AECs
secrete increased quantities of IL-8 in response to other
pathogens as well, such as human rhinovirus (31). There are
other broad differences in Cftr-deficient AECs that seem to
exacerbate neutrophil-mediated inflammation. Cftr-deficient
AECs also produce less glutathione (32, 33) but have higher
levels of COX2 and prostaglandin E2 (34, 35). Glutathione is
critical for neutralizing the damaging reactive oxygen species
produced by oxidative processes in response to infection,
whereas prostaglandins produced by COX2 are responsible
for mediating a broad spectrum of inflammatory processes.
Coupled with excessive numbers of neutrophils, these condi-
tions are a recipe for havoc in the CF lung (Figure 1).
Cftr appears to maintain homeostatic expression of up to 843
genes, according to one study in cultured human AECs (36),
and 702 to 943 genes in a mouse study (37). When grouped, the
majority of these genes were found to be involved in phago-
cytosis, complement activation, apoptosis, DNA replication,
T-cell selection, B-cell activation, and chemotaxis. By what
mechanism does CFTR, a chloride channel, affect all of these-
Several groups have proposed that Cftr has physiological roles
besides chloride conductance. Some researchers have shown that
Cftr interacts with b-adrenergic receptors (38), phoshodiesterases
(39), and other ion channels (40, 41). The significance of these
interactions is open to speculation, although it is likely that addi-
tional signaling pathways are affected.
Balghi and colleagues (42) recently proposed a new model in
AECs that may explain many if not all of these alterations. They
showed nearly 2-fold elevation in the expression of ORAI1, which
is a Ca21release–activated Ca21channel in the cell membrane, in
Cftr-deficient AECs. They also measured a 2-fold increase in the
calcium ICRACcurrent in these cells, a 2-fold increase in total
intracellular Ca21, and a 2-fold increase in the secretion of IL-8.
The ICRACcurrent was normalized by increasing CFTR levels at
the cell surface. Their data demonstrate that store-operated cal-
cium entry is excessive in Cftr2/2cells; this can lead to inappro-
priate cytokine expression by Ca21–sensitive gene expression
Although many important lessons have been learned from
studies of CFTR in AECs, data are emerging that a primary
CFTR defect in cells of the innate immune system contributes
significantlytoCF lungpathology. Whenhealthymice arerecon-
stituted with Cftr2/2neutrophils, they develop severe lung in-
flammation and injury upon LPS challenge compared with mice
receiving wild-type neutrophils (43); this inflammation is driven
by increased NF-kB transcription, which seems to be increased
in multiple Cftr-deficient cell types. Because neutrophils are the
first line of defense against P. aeruginosa infection, proper neu-
trophil function is critical in patients with CF and warrants
One question that has been posed is whether CFTR mutation
disrupts phagolysosomal function in neutrophils. Morris and col-
leagues (44) showed that CF neutrophils from patients with CF
have a reduced phagocytotic capacity, although the authors
could not detect CFTR by Western blot; indeed, some still
question whether CFTR is expressed in neutrophils at all. It is
not clear if the phagocytic defect is intrinsic to neutrophils, but
this group suggests the possibility that mutant CFTR may be
expressed during neutrophil maturation in the bone marrow and
causes an irreversible functional defect. This notion is supported
by the observation that a human leukemic cell line up-regulates
CFTR when induced to differentiate into neutrophils (45).
Others have also reported a defect in CF neutrophil respiratory
burst, attributed to disrupted chloride transport to the phagoly-
sosome (45–48). Studies in zebrafish have confirmed this finding
as well (49).
CFTR plays a role in early neutrophil development, as is sug-
gested by the fact that other cells of the granulocyte lineage be-
have peculiarly in CF. A recent study demonstrated that
subpopulations of mast cells are present at an altered ratio in
the lungs of patients with CF (50). These CF mast cells secrete
increased levels of IL-6, a proinflammatory cytokine that stim-
ulates neutrophil production in the bone marrow and inhibits
the activity of regulatory T cells. Little is known about the
activity of CFTR in hematopoietic stem cells or its effect on
differentiation. To expand on this theme, CF platelets have
been shown to be more readily activated than non-CF platelets,
and this can contribute to the recruitment of neutrophils to the
lung and other inflamed tissue (51, 52). This activation is not
directly due to the lack of platelet CFTR but rather is due to CF
plasma factors as well as perhaps intrinsic changes in gene ex-
pression in the hematopoietic stem cell lineage. Nevertheless,
this is further evidence for a systemic hyperinflammatory state
not limited to the lung.
Putting these anomalies in perspective, it has been found that
in neutrophils alone (53); these genes include signal transduc-
tion molecules, interleukin receptors, chemokines, and all three
716AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL 462012
colony-stimulating factors (G-, M-, and GM-CSF). Recently,
miRNAs have joined the growing list of disturbed pathways in
CF, where 5-fold higher levels of miR-155 in CF AECs and neu-
trophils result in up-regulation of the PI3K/Akt signaling path-
way (54); alterations in this broad signaling pathway would be
difficult to predict but would be expected to have a significant
impact on cell behavior.
Other interesting changes in neutrophil physiology have been
documented. One group observed that toll-like receptor 4
(TLR4) is up-regulated in CF neutrophils, whereas TLR2 is
down-regulated (55); this could compromise the effectiveness
of the innate immune response in clearing pathogens and result
in dysregulation of inflammatory pathways. Similar findings
have been observed in the CF monocyte lineage.
Another group recently found that the expression of Annexin
A1, an endogenous antiinflammatory protein, is controlled by
a CFTR-dependent pathway and that addition of recombinant
Annexin A1 to CF mice corrects the exaggerated neutrophil mi-
gration to the pancreas (56). It would be interesting to see if
Annexin A1 can also correct the abnormal leukocyte migration
to the CF lung and whether the corrected neutrophils are able
to adequately respond to pathogens.
and remains to be fully elucidated. The practical measure for the
competence of CF neutrophils lies not in the variation in cyto-
kines but rather in their ability to clear infection. Despite the en-
suing pulmonary inflammation with associated mortality, CF
mice are able to clear acute P. aeruginosa infection in approx-
imately the same time as wild-type mice (20, 24, 57), but they
are unable to clear chronic infection. This compels us to sepa-
rately recognize two aspects of the lung pathology: the excessive
inflammatory response and the inability to clear chronic infec-
tion. In both cases, it may be that mutant CFTR impairs the
ability of the adaptive immune system to clear chronic bacterial
infection and to halt the excessive neutrophil inflammation.
In summary, CFTR appears to affect multiple gene expres-
sion pathways in AECs and neutrophils, and the effects from
both cell types complement one another to produce excessively
destructive inflammation in the CF lung. We have learned that
increased intracellular Ca21levels can alter the expression of
many genes in affected CF cells, with possible impact on the
ability to clear pathogens and on the severity of the inflam-
matory response. CFTR-associated perturbations in intracel-
lular Ca21may have direct effects on a variety of immune cells.
CFTR IN MONOCYTES AND MACROPHAGES
Alveolar macrophagesmature from circulating blood monocytes
and play a major role in the direct clearance of pathogens in
the lung as well as the presentation of antigens to helper
T cells. Some investigators have hypothesized that their func-
tion is compromised in CF because patients are unable to clear
chronic infection with P. aeruginosa and have worse outcome
in P. aeruginosa sepsis compared with patients without CF.
pathogens. Originally this was suggested to be due to defective
opsonization and phagocytosis (58–60). Although this may be
a contributing factor, the percentage of surviving bacteria is in-
creased in CF macrophages even after successful phagocytosis
(61). The implication is that a pathogen-killing defect is also
present, although it is not immediately clear whether this is due
to an intrinsic macrophage defect or the aberrant signaling of
Some groups have proposed that CFTR mutation disrupts
phagosome acidification in macrophages, thus compromising
the lysis of pathogens (62, 63). They showed that the capacity
for phagocytosis and lysogenic fusion is preserved in the CF
macrophage. However, in 2007 Haggie and Verkman provided
pharmacological evidence showing that Cftr does not partici-
pate in acidification of the phagosome and attributed the obser-
vation of the former group to a conceivable artifact of the
pH-sensitive dye that was used in the experiment (64). To-
gether, these studies seem to suggest that the pathogen-killing
machinery in CF macrophages is grossly intact. Therefore, mu-
tant CFTR must be compromising pathogen-killing via another
mechanism, perhaps by inhibiting macrophage activation. Evi-
dence suggests that this speculation is worth investigating be-
cause, although the numbers of macrophages, neutrophils, and
CD31 T cells in CF lungs are elevated (16), the number of
activated macrophages and neutrophils is reduced (65). One
possibility is that mutant CFTR causes the accumulation of
calcium levels sufficient to affect gene expression within the
macrophage. Recently, Shenoy and colleagues showed that in-
tracellular Ca21levels do increase in wild-type monocytes trea-
ted with inhibitors of CFTR and Ca21ATPase (66), which
warrants investigation into how macrophage gene expression
may be affected.
We learned from studies in AECs and neutrophils that Cftr
affects a broad range of cell processes. As in other CF cell types,
there appear to be aberrations in the gene expression pathways
of CF monocytes, which could compromise their ability to clear
pathogens. Zaman and colleagues demonstrated that the
MAPK/Erk pathway is hypersensitive to stimulation by LPS
in homozygote and even in heterozygote CF monocytes (4).
This would have significant consequences for immune function
because the MAPK/Erk pathway is involved in critical cell func-
tions (e.g., cell division, apoptosis, and cytokine synthesis).
Moreover, they found that CF monocytes produce 100-fold less
IL-8 in response to LPS stimulation compared with controls,
which implies decreased neutrophil recruitment to sites of in-
fection by gram-negative bacteria. This could be significant dur-
ing sepsis, where recruitment of neutrophils to the infectious
source is critical to stop the spread of the pathogen. Bruscia
and colleagues showed that LPS hypersensitivity in CFTR-
deficient monocytes is due to ineffective turnover of TLR4,
which is caused by delayed transfer to the lysosomal compart-
ment from the early endosome (67). This is further supported by
evidence of increased expression of TLR4 in monocytes of chil-
dren with CF even in the absence of infection (68). The conse-
quence of this in patients with CF appears to be an exaggerated
inflammatory response upon encountering LPS but reduced
overall effectiveness in clearing the pathogen. It is also worth
questioning whether the up-regulation of TLR4 may allow
more adjuvant-mediated hypersensitivity reactions to occur
against antigens that would otherwise be tolerated in healthy
Another group found that peripheral blood monocytes from
(69). The authors attribute this observation to the 2-fold lower
levels of TREM1 in circulating CF monocytes, which is a down-
stream signaling protein important in leukocyte activation. The
signaling events downstream of TREM1 are not well character-
ized, but Gibot and colleagues recently showed that TREM1
enhances survival during septic shock in mice (70). Furthermore,
the increased activity of macrophage inhibitory factor in patients
with CF may also contribute to an ineffective response against
pathogens (71). In future studies, these findings may aid in form-
ing hypotheses for why patients with CF have poor clinical out-
come in P. aeruginosa pulmonary infection and sepsis.
Although the anomalies in CF monocytes and macrophages
seem to be due at least in part to an intrinsic CFTR defect, their
function may be further compromised by disrupted processes
Red in Translation717
elsewherein theCFimmunesystem.For instance, a lack of mac-
rophage activation by helper T cells may allow chronic P.
aeruginosa infection to persist (Figure 1). The adaptive im-
mune system likely plays an important role in CF macrophage
pathology, although relative contributions of an intrinsic de-
fect in macrophages and other cells have been difficult to dissect.
Nevertheless, CFTR is expressed in T cells, and aberrations in
these cells may have anywhere from subtle to profound effects on
immune function systemically.
CFTR IN LYMPHOCYTES
One aspect that continues to be enigmatic in CF is the observed
alteration in adaptive immune responses to certain pathogens.
Patients with CF have a tendency toward allergic reactions,
asthma, dermatitis, and hyperinflammatory immune responses.
Although lymphocytes have never been directly established as
the cause of these phenomena, this pattern makes one wonder
review, an investigator pointed out that stimulation of wild-type
l light chain secretion, but this effect is absent in CF B cells
(72). A failure of regulated secretion could cause a reduced
response to antigen presentation and an inability to clear P.
aeruginosa infection, which leads to loss of lung function.
has been known since the late 1970s (73–79), and recent
insights are beginning to shed some light on these observa-
tions. Central to the CF T-cell phenotype appears to be a pre-
dilection to mount a type 2 helper T-cell (Th2) response (80),
which is proallergic and appropriate for fighting parasites, but
not pathogens such as P. aeruginosa. Indeed, clinical data show
that approximately 10% of patients with CF develop allergic
bronchopulmonary aspergillosis upon exposure to A. fumigatus
(13, 81), with increased levels of IL-4, IL-13, and IgE in what
appears to be a hyperinflammatory, Th2-dominated immune re-
sponse (82). In CF mice, increased levels of IgE are observed
compared with controls after exposure to A. fumigatus (83,
84), accompanied by a significant shift to a predominantly
IL-4 and IL-13 cytokine profile and a greater sensitivity of
CF B cells to IL-4 stimulation (85). Our group confirmed that
this is due to the lack of functional Cftr in T cells by recapit-
ulating the exaggerated IgE levels in T cell–specific CFTR
knockout mice and in immunodeficient mice that were trans-
planted with CF splenocytes (3). These findings establish a role
of Cftr-deficient lymphocytes in causing allergic inflammation
in CF, but more importantly they reveal the capacity of CF
T cells to misorchestrate the immune response to pathogens.
This may severely compromise the ability of individuals with
CF to efficiently clear P. aeruginosa and could allow infection
by B. cepacia and other unusual pathogens.
There is evidence that T-cell and macrophage unresponsive-
ness to P. aeruginosa may be the result of Th2 skewing in CF.
Moss and colleagues showed that helper T cells from patients
with CF produce lower levels of IFN-g, a Th1 cytokine, and
higher levels of IL-10, a Th2 cytokine (86). IL-10 expression
in CF has been a subject of debate, but it has been confirmed
to be up-regulated by Casaulta and colleagues (87). This is in-
teresting because the ability of IL-10 to down-regulate IFN-g
production and decrease costimulatory molecules on macro-
phages can hinder antigen presentation and a proper immune
response to P. aeruginosa, A. fumigatus, and other pathogenic
Figure 1. Snapshot of the cystic fibrosis (CF) immune system and pro-
cesses affected by mutant cystic fibrosis transmembrane conductance
regulator (CFTR). This diagram shows the complex interaction between
various cell types, all of which lack CFTR and may have an independent
phenotype. Epithelial cells secrete IL-8 and other chemokines that at-
tract neutrophils to the lung, potentiating inflammation especially in
the setting of bacterial infection. The intrinsic effect of CFTR deficiency
in neutrophils and macrophages appears to be an inability to effectively
kill bacteria. This is further exacerbated by inadequate Th1 activation of
macrophages by CFTR-deficient helper T cells, which seem to favor
a proallergic Th2-type response upon activation. This leads to increased
IL-4 and IL-13 levels, which stimulate IgE antibody synthesis by B cells. IgE
on mast cells potentiates allergy and inflammation, and CFTR-deficient
mast cells overproduce the proinflammatory cytokine IL-6. This excessive
inflammatory response is particularly damaging in the CF lung because
CFTR-deficient epithelial cells produce decreased levels of glutathione and
increased amounts of proinflammatory prostaglandins.
Figure 2. Proposed model showing how the lack of functional CFTR
and resultant hyperpolarization of the helper T-cell membrane leads
to increased Ca21entry upon activation of the T-cell receptor. This
results in the opening of calcium-gated Ca21channels and Ca21–
mediated activation of the NFAT transcriptional pathway. The final
result is increased expression of proinflammatory cytokines, charac-
teristic of a Th2-type immune response.
718 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGYVOL 462012
species. Further studies are needed to establish if antigen pre-
sentation by macrophages is indeed compromised.
A Th1immune response maybecritical for successfullyclear-
ing P. aeruginosa infection. Moser and colleagues showed that
when CFTR2/2mice are repeatedly infected with P. aeruginosa,
recovery from infection is accompanied by a shift to a Th1 re-
sponse and increased levels of IL-12 but no change in IgG lev-
els (88). The surviving mice are resistant to reinfection and have
improved survival. CF mice colonized with P. aeruginosa have
a higher antibody titer against P. aeruginosa antigens than do
colonized wild-type mice but still develop chronic infection (89).
This suggests that a Th1-type immune response is protective
against P. aeruginosa infection independent of antibody produc-
tion and compels us to examine the mechanism of a CFTR-
mediated defect in T cells, which seems to favor inappropriate
One emerging explanation for the phenomenon of Th2 skew-
ing is the hypothesis that mutant Cftr causes increased Ca21flux
across the T-cell membrane, thereby perturbing Ca21–sensitive
gene expression pathways. Ca21influx is known to be critical
for T-cell activation and is tightly regulated by a number of ion
channels, including Cftr (42). Disruption of this delicate balance
could lead to abnormal expression of many genes in T cells,
including those responsible for Th1/Th2 differentiation. Our
group found increased intracellular Ca21entry in helper T cells
of CF mice upon T-cell receptor stimulation, followed by in-
creased translocation of the transcription factor NFAT into the
nucleus (Figure 2) (3). NFAT is known to drive the expression
of Th2 cytokines, including IL-4, IL-13, and IL-6 (90–92), which
lead to IgE synthesis and inflammation.
Different isoforms of NFAT promote different cytokine ex-
pression profiles and determine helper T-cell–type differentia-
tion. In particular, the balance between NFATc1 and NFATc2
appears important in determining T-cell differentiation (93).
Unchecked NFATc1 activity promotes Th2 differentiation and
production of IL-4, IL-5, and IL-6 in helper T cells and ex-
tremely high levels of IgE in B cells. IL-4 and IgE are overex-
pressed in individuals with CF, with an associated skewing
toward Th2 differentiation. Few studies have been conducted
exploring the regulation of cytokine expression by NFAT iso-
forms in Cftr-deficient T cells or their potential dependence on
Although the downstream effects of Cftr dysfunction are im-
portant, it is events at the cell membrane that drive the Cftr-
mediated gene expression aberrations in T cells and warrant
further attention. In 2001, Fanger and colleagues (94) showed
that Ca21entry in Jurkat T cells resulted in activation of KCa
channels, creating an efflux of K1ions, which prevents cell
membrane depolarization and allows continued Ca21entry;
these Ca21levels are sufficiently high to cause the signaling
necessary for transcriptional activation. If so, then defective
Cftr function and subsequent intracellular retention of Cl2ions
would be expected to further hyperpolarize the T-cell mem-
brane and augment Ca21–activated signaling. Because it is pos-
sible that defective Cftr function may further hyperpolarize the
T-cell membrane, ostensibly by intracellular retention of nega-
tively charged chloride ions, Ca21–activated signaling may be
augmented in CF T cells (Figure 2). The Orai1/Stim1 complex is
also present in the T-cell membrane. Studies are needed to
determine whether it is similarly affected by mutant Cftr and
leads to abnormal gene expression.
Recent insights in T-cell electrophysiology are also giving
new perspective to local Cftr functions in the T-cell membrane.
According to Cahalan and Chandy (40), some ion channels
(Orai1, STIM1, Kv1.3, and KCa3.1) cluster at the antigen pre-
sentation site after contact with an antigen-presenting cell
(APC). They hypothesize that this clustering could be impor-
tant for stabilizing the interaction between the T cell and the
APC and in generating large extracellular K1concentrations
sufficient to depolarize the APC and the T cell. This may be
important for efficient antigen presentation because MHC class
II molecule expression on dendritic cells has been shown to
double within 1 minute of K1–induced depolarization (95).
The downstream effects of this may be speculated; regardless,
these mechanisms may be affected by the lack of functional Cftr
at the cell membrane.
CF is a systemic disease where multiple organ systems are affected
with much overlapping pathology. Isolating the pathologic mecha-
gene expression. This is of particular concern in helper T cells
because signaling abnormalities in these cells could manifest them-
selves clinically as vague comorbidities (e.g., allergy, dermatitis)
alongside more prominent CF symptoms. These can be easily
overlooked in the context of life-threatening lung infections or
attributed to malnutrition. In fact, mutant Cftr in helper T cells
could account for much of the mortality of patients with CF due to
the less effective performance of the immune system as a whole
(Figure 1). Efforts to develop therapeutic strategies for CF should
encompass immune cells as well as other cell types. In particular,
Ca21channels may be attractive drug targets in light of recent
data on the dysregulation of store-operated calcium entry and
perturbation of Ca21–sensitive gene expression pathways in CF.
One major question that remains for the field is the degree to
which immune dysfunction accounts for CF mortality, as com-
pared with CFTR-related defects in AECs. This is critical to
establish to best focus resources on an effectively targeted treat-
ment strategy. Because lung-directed treatments short of trans-
plantation have little appreciable effect in the long-term survival
and quality of life of patients, an alternative approach aimed at
The recent years have been pivotal in our understanding of
CF because a cause-and-effect relationship has been established
between ion transport and gene expression in CF immune cells.
As the details of this mechanism and their greater impact on im-
mune function continue to be elucidated, we can only hope that
these findings will advance clinical efforts to treat this disease
and improve the duration and quality of life for patients.
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgments: The authors thank Brian O’Sullivan for his critique and help in
preparing this manuscript.
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