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*
Mayo Clinic, Department of Immunology, Rochester, MN 55902; and
Novartis Horsham Research Centre, Horsham, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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.
Flow-cytometric analysis of cytokine-producing cells in peritoneal
lavage fluid revealed increased numbers of IL-5-producing cells in both
T cell and NK cell populations following allergen exposure. Depletion
of NK cells by treatment with NK1.1 Abs selectively reduced the number
of infiltrating eosinophils by more than 50%. Moreover, the inhibition
of the infiltration of eosinophils was accompanied by a complete loss
of IL-5-producing NK cells and significantly reduced levels of
peritoneal lavage fluid IL-5, whereas the number of IL-5-producing T
cells was not affected. Thus, the results presented in this study
provide clear evidence for a novel immunoregulatory function of NK
cells in vivo, promoting allergen-induced eosinophilic inflammatory
responses by the production of IL-5. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Allergen-specific CD4+ Th2 cells producing IL-4, IL-5, and
IL-10, but no IL-2 or IFN-, are currently regarded as the key
regulatory cells controlling allergic eosinophilic inflammatory
responses (11, 12, 13, 20, 21, 22). For example, in atopic individuals,
allergen-specific T cell clones produce a Th2-like pattern of
cytokines, whereas other Ag-specific T cell clones from the same
patients have a Th1-like pattern of cytokine production, secreting IL-2
and IFN-, but no IL-4 or IL-5 (20). Furthermore, the infiltrating
cells in allergen-induced late phase skin reactions, as well as after
segmental allergen challenge in the lung of asthmatic and rhinitis
patients express mRNA and produce proteins for IL-3, IL-4, IL-5, and
GM-CSF, but not for IL-2 or IFN- (9, 12, 13). Moreover, it has been
demonstrated that the development of Ag-induced pulmonary eosinophilia
and airway hyperresponsiveness in murine models of allergic
inflammation is closely associated and dependent on CD4+ T
cells producing a Th2 cell type pattern of cytokines. Administration of
anti-CD4 Abs before Ag challenge completely prevented these
responses (23, 24).
On the other hand, recent studies have demonstrated that human NK cells
can be induced to produce IL-5 in vitro, suggesting that these cells
may contribute to the development of eosinophilic inflammation (25, 26). Cytokines produced by NK cells have indeed been shown to play
important immunoregulatory functions in the early responses to viral,
bacterial, and parasitic infections, as well as in the development of T
cell responses to these infectious agents (27, 28). For example, it is
well established that NK cells are major producers of IFN- in vivo,
thereby directing the differentiation of Th cells into IL-2- and
IFN--producing Th1-type cells (29, 30, 31, 32, 33, 34). However, several in vitro
studies have demonstrated that polarizing stimuli such as IL-4 and
IL-12 profoundly affect the cytokine pattern produced by NK cells (25, 26). The production of IFN- in cultures of purified peripheral blood
NK cells was inhibited by IL-4, but significantly enhanced by IL-12. In
contrast, IL-4 augmented, whereas IL-12 inhibited the production of
IL-5. Thus, similar to the generation of Th1 or Th2 cells, cytokines
present in the local microenvironment may differentially affect the
development of distinct cytokine-producing NK cell subsets.
Consequently, one set of cytokines released by NK cells (IFN-) may
favor the development of a characteristic Th1-type immune response,
whereas other cytokines such as IL-5 may contribute to eosinophilic
inflammation. However, whether NK cells produce IL-5 in vivo and
thereby contribute to the development of eosinophilic inflammatory
responses is not yet known. To address this question, we analyzed the
distribution and cytokine production of NK cells in a well-established
murine model of allergic inflammation, known to be associated with a
selective tissue accumulation of eosinophils (35, 36, 37). The data
presented in this study clearly demonstrate that NK cells indeed
produce IL-5 in vivo, and thereby exert an important regulatory
function in allergen-induced eosinophilic inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice (females, 18 to 25 g, 6 to 8 wk of age) were obtained from The Jackson Laboratory (Bar Harbor, ME). Mice were immunized s.c. with short ragweed Ag extract (1/10,000 dilution; Greer Laboratories, Lenoir, NC) in 0.2 ml of saline containing penicillin/streptomycin (50 U/ml and 5 µg/ml, respectively; Sigma, St. Louis, MO) on days 1 and 8. Sham-immunized mice received two injections of saline alone. Seven days after the last immunization (day 15), animals were challenged by i.p. injection of 0.2 ml ragweed Ag extract. Saline- or ragweed-immunized control groups received an i.p. injection of 0.2 ml of saline. Forty eight hours after the Ag provocation, animals were killed and peritoneal lavages were performed with 3 ml of HBSS (without Ca2+ and Mg2+; Celox, Hopkins, MN) containing 0.1% BSA (Sigma). Total cell numbers and leukocyte differentials were performed as described below. Lavages were centrifuged and supernatants were frozen at -20°C until use for cytokine measurements.
Depletion of NK cells
Mice were depleted of NK cells by i.v. administration of anti-mouse NK1.1 mAbs (30 µg/mouse/day; PharMingen, San Diego, CA) either before allergen challenge (days 14 and 15) or both during immunization and before challenge (days -1, 0, +1, 14, and 15). Control groups of mice received an isotype-matched control mAb (mouse IgG2a, 30 µg/mouse/day; PharMingen) at the same time intervals.
Determination of total cells and leukocyte differentials
The total nucleated cell count was determined microscopically following staining of peritoneal lavage cells by Randolph’s stain, and calculated as total cells per recovered volume. Cytologic examinations of peritoneal lavage cells were done after cytocentrifugation and staining with May-Gruenwald-Giemsa. The relative proportions of the various leukocyte subpopulations were determined by a cell differential count of 1000 cells.
Quantitation of cytokines in peritoneal lavage fluid
IL-5, IL-4, and IFN- were measured by sandwich ELISA using
two mAbs recognizing different epitopes of the specific cytokine. Abs
used for measuring IL-5 (TRFK5 and biotinylated TRFK4), IL-4 (BVD4-1D11
and biotinylated BVD6-24G2), or IFN- (R4-6A2 and biotinylated
XMG1.2) were all purchased from PharMingen. In all cases, binding of
the second Ab was analyzed by stepwise incubation with
streptavidin-alkaline phosphatase conjugate (Mabtech, Stockholm,
Sweden) and 4-nitrophenylphosphate disodium salts (Sigma). OD was
measured at 405 nM, and cytokine concentration was calculated based on
the results from serial dilutions of standard recombinant mouse IL-5,
IL-4, and IFN-, respectively. The sensitivity of the cytokine ELISAs
was about 10 pg/ml.
Determination of lymphocyte subpopulation by immunofluorescence
Specific binding of mAbs was analyzed by direct immunofluorescence using a FACScan flow cytometer (Becton Dickinson, Mountain View, CA). Briefly, 1 x 105 cells in staining buffer (PBS containing 2% FCS and 0.1% sodium azide) were incubated in the presence of saturating concentrations of CyChrome-conjugated anti-CD3 mAb and FITC-conjugated anti-pan NK or NK1.1. mAbs (PharMingen) in the dark on ice for 30 min. Cells were then washed twice with staining buffer and fixed with a 1% paraformaldehyde solution (pH 7.4 in PBS). Cytofluorometric analysis was performed using laser excitation at 488 nm, and the number of immunofluorescence-positive cells was determined per 10,000 analyzed cells. Specific binding of mAbs was controlled by subtraction of isotype-matched control Abs.
Determination of cytokine-producing lymphocyte subpopulation
Cytokine-producing peritoneal lavage cells were determined as
recently described (38). Briefly, peritoneal lavage cells were
incubated for 4 h at 37°C in RPMI containing 10% FCS and
brefeldin A (10 µg/ml; Sigma) to disaggregate the Golgi complex,
enabling newly synthesized proteins to accumulate intracellularly (39).
Cells were then washed with PBS and incubated for 30 min at 4°C with
optimal concentration of CyChrome-conjugated anti-CD3 mAb and
FITC-conjugated pan NK or NK1.1. mAbs (PharMingen). In some
experiments, the anti-CD3 Ab was replaced by a mixture of
anti-
/ß and /
TCR mAbs (Fig. 7
; PharMingen). Cells were
washed again and fixed in 100 µl solution A (Fix & Perm cell
permeabilization kit; Caltag Laboratories, San Francisco, CA) for 15
min at room temperature, washed in PBS, and resuspended in 100 µl of
permeabilization solution B (Fix & Perm kit; Caltag Laboratories)
containing phycoerythrin-labeled anti-IL-5 (TRFK5),
anti-IFN- (4S.B3), or isotype-matched control Abs (all purchased
from PharMingen). Cells were incubated for another 15 min at room
temperature, washed in PBS, and immediately analyzed using a FACScan
(Becton Dickinson, San Jose, CA). Specificity of the staining was
controlled by isotype-matched control mAbs and by preincubation of the
permeabilized cells with nonconjugated anti-IL-5 or
anti-IFN- mAbs before adding the phycoerythrin-conjugated
anti-cytokine mAb, reducing the specific immunofluorescence signal
to background levels.
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Statistical anlysis was performed using the two-tailed Mann-Whitney U test. Differences associated with probability values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intraperitoneal injection of Ag in short ragweed Ag-immunized mice
induced an infiltration of various leukocytes into the peritoneal
cavity (Table I). Significantly increased
total numbers of eosinophils, lymphocytes, neutrophils, and macrophages
were found in allergen-challenged mice compared with the nonimmunized
or sham-challenged group with the most pronouced change in the number
of eosinophils. Both the absolute as well as the relative numbers of
eosinophils were increased significantly in allergen-challenged mice
(1.1% ± 0.1 in naive, 5.9% ± 0.7 in nonchallenged, and 23.7% ±
1.4 in challenged mice), whereas the relative numbers of lymphocytes,
neutrophils, or macrophages were not changed or decreased.
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). The concentration of IFN-, mainly
produced by Th1 and NK cells, was also increased in the peritoneal
cavity from these animals. However, the absolute IFN- concentration
after allergen challenge was considerably lower compared with the
levels of IL-4 or IL-5. Taken together, i.p. provocation of actively
immunized C57BL/6 mice with ragweed Ags induced a selective
accumulation of eosinophils in the peritoneal cavity and the production
of a predominantly Th2 cell type cytokine pattern, both characteristic
features of an allergic inflammatory response.
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To identify the cellular source for the increased levels of Th1
and Th2 cell type cytokines present in peritoneal lavages after
allergen provocation, the total number and cytokine-producing T cells
and NK cells were determined using immunofluorescence-staining
techniques and flow cytometry. First, the number of T cells and NK
cells present in peritoneal lavage fluids from the various groups of
ragweed-sensitized and -challenged mice were determined by staining
peritoneal lavage cells with mAbs directed against CD3 or against the
NK cell marker NK1.1. Double fluorescence analysis of lymphocytes from
these animals revealed the presence of three clearly separable
populations of Ab-stained lymphocytes, a CD3-positive, NK1.1-negative T
cell population, a small population of double-positive T cells, as well
as a population of CD3-negative NK1.1.-positive cells representing NK
cells. As shown in Figure 1, all three
subpopulations of lymphocytes were increased significantly in
peritoneal lavage fluids from ragweed-challenged mice, with the most
pronounced relative increase in the number of NK cells. These results
suggest that all three cell types may participate in the regulation of
an eosinophilic inflammation. This is further supported by the fact
that T cells, NK1.1.-bearing T cells, as well as NK cells were all
shown to be capable of IL-5 production in vitro (20, 21, 22, 26, 26, 40, 41).
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and 3). Figure 2 shows a representative
example of a three-color immunofluorescence used to determine the
number of IL-5-producing T and NK cells. Based on their expression of
CD3 or NK1.1 Ags, cells were electronically separated into
CD3-expressing T cells and CD3-negative NK cells (Fig. 2A),
followed by analysis of their fluorescence profile after staining with
either anti-IL-5 or isotype-matched control Abs. The
immunofluorescence signal obtained from anti-IL-5-stained T cells
(Fig. 2C) and NK cells (Fig. 2E) was clearly
separable from the measurements of Ig isotype-matched control samples
(Fig. 2, B and C) and completely inhibitable by
preincubation of the permeabilized cells with unconjugated
anti-cytokine Abs (data not shown), clearly demonstrating the
presence of IL-5-producing T cells and NK cells in peritoneal lavages
from ragweed-challenged mice. As shown in Figure 3, peritoneal lavage
fluids obtained from these allergen-exposed mice contained
significantly increased numbers of IL-5-producing T cells and NK cells
as compared with ragweed-sensitized, saline-challenged animals. Thus,
both T cells and NK cells produce IL-5 in response to allergen exposure
in vivo, and may thereby contribute to the Ag-induced, IL-5-mediated
tissue accumulation of eosinophils. Similar results were obtained by
analyzing the number of IL-5-producing, NK1.1.-expressing CD3 cells,
which were elevated significantly following allergen exposure
(0.19 x 103 in nonchallenged mice vs 1.01 x
103 in ragweed-challenged mice). However, due to the low
number of IL-5-expressing cells within this lymphocyte subpopulation,
this type of analysis was not feasible in all analyzed mice.
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To further analyze whether IL-5 derived from NK cells contributes
to the ragweed Ag-induced eosinophil infiltration, C57BL/6 mice were
treated with anti-mouse NK1.1 mAbs, a well-established method to
deplete NK cells in mice (44, 45, 46). Abs against NK1.1 or isotype-matched
control Abs were administered i.v. either shortly before the ragweed
challenge or before both the immunization and challenge procedures.
Figure 4 shows a representative
flow-cytometric measurement from cells stained with anti-CD3 and an
anti-NK cell Ab obtained from ragweed-challenged, NK1.1.-treated
and -challenged, or control Ab-treated and -challenged mice. Treatment
with NK1.1. Abs completely depleted the CD3-negative NK cell
population, whereas a significant proportion of the double-positive
CD3/NK1.1-expressing T cells remained present. This is also shown in
Figure 5, demonstrating that NK cell
depletion by NK1.1. Abs did not alter the number of CD3-expressing T
cells (Fig. 5A), whereas the number of NK cell Ags
expressing CD3-positive T cells (Fig. 5B) was significantly,
but not completely, reduced. Similar results were obtained by staining
the cells with either fluorescent labeled NK1.1. Abs or a pan NK cell
marker that recognizes a different molecule on NK cells with a very
similar cell distribution compared with NK1.1. (data not shown).
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, treatment with NK1.1,
but not isotype-matched control Abs resulted in a significant and
selective reduction of eosinophils present in peritoneal lavages
obtained from ragweed-challenged and -immunized mice. The total cell
numbers as well as the number of lymphocytes were slightly decreased,
whereas a slight increase of macrophages was observed in these NK
cell-depleted mice. Furthermore, no differences were found by comparing
the effect of NK1.1. treatment before challenge or during immunization
and challenge, suggesting that the main eosinophil active effect of NK
cells takes place directly in response to the allergen challenge.
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To further analyze whether the depletion of NK cells was also
accompanied by a reduced number of IL-5-producing cells and diminished
levels of IL-5, peritoneal lavages obtained from NK cell-depleted and
allergen-sensitized and -challenged mice were analyzed for their
content of cytokines as well as IL-5- and IFN--producing T cells and
NK cells. As shown in Table III,
depletion of NK cells significantly reduced the concentration of IL-5,
IL-4, and IFN- in peritoneal lavage fluid from allergen-challenged
mice. The inhibition of IL-5 was much more pronounced compared with the
changes of IL-4 and IFN- levels. Again, no effect was found in
control Ab-treated animals, and no significant differences were
observed by comparing the effect of NK1.1. treatment before challenge
or before immunization and challenge. Moreover, analysis of
cytokine-producing T cells and NK cells clearly demonstrated that
treatment with NK1.1 Abs completely eliminated the total number as well
as the IL-5- and IFN--producing NK cells in the peritoneal cavity
(Fig. 7
, B, D, and
F). In contrast, the total number as well as the proportion
of cytokine-producing T cells was not altered significantly by the Ab
treatment (Fig. 7, A, C, and E),
suggesting that NK cells directly affect the allergen-induced tissue
accumulation of eosinophils by the production of IL-5 without
inhibiting cytokine release from T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is thought to play an important role in
immune responses against various pathogens by determining the
differentiation of Ag-specific Th cells producing a Th1 cytokine
pattern with IL-2 and IFN-, but no IL-4 or IL-5 (27, 28, 29, 30, 31). However,
the recent description of IL-5 production by human NK cells in vitro
raised the question as to whether these cells produce a distinct,
polarized cytokine profile similar to Th1 and Th2 cell types, and
thereby contribute to allergen-induced eosinophilic inflammatory
responses (25, 26). To answer this question, we analyzed the
distribution and cytokine production of NK cells in a ragweed-induced
murine allergic peritonitis model. The results presented in this study
provide clear evidence for the presence of IL-5-producing NK cells in
vivo. Moreover, depletion of NK cells not only reduced the levels of
IL-5 in peritoneal lavage fluid, but also selectively inhibited the
infiltration of eosinophils into the peritoneal cavity following
allergen challenge. Thus, these results clearly indicate that NK cells
have indeed the capacity to regulate tissue accumulations of
eosinophils by overproduction of IL-5.
The results obtained with the ragweed allergen-induced murine allergic
peritonitis model confirm earlier studies using other mouse strains
and/or other allergens (35, 36, 37). In those studies, i.p. allergen
challenge of sensitized mice also resulted in a massive accumulation of
eosinophils within the peritoneal cavity, which was associated with
increased levels of IL-5 and IFN-. In addition, treatment with
neutralizing anti-IL-5 mAb completely inhibited the tissue
accumulation of eosinophils (35, 37), demonstrating the IL-5 dependency
of this allergic eosinophilia.
Many studies have focused on identifying the cellular source of IL-5 in allergic inflammation. CD4+ and CD8+ T cells, mast cells, and eosinophils have all been shown to be capable of IL-5 production in vivo and in vitro (47, 48, 49, 50). With regard to T cell subsets, CD4+ cells appear to be a much more important source for IL-5 than CD8+ T cells. This could be demonstrated in experiments in which mice were depleted of CD4- or CD8-positive T cells by treatment with specific Abs (23, 24, 37). Under these conditions, Ag-induced IL-5 release and eosinophil infiltration into the mouse bronchial tissue of peritoneal cavity were suppressed in CD4, but not CD8, T cell-depleted animals, supporting the concept of an IL-5 and CD4 T cell dependency of eosinophilic inflammations in mice. Similar conclusions were reached from clinical studies with patients with asthma, in which IL-5 produced in the bronchial mucosa appeared to be mainly associated with CD4+ T cells, and the CD4 T cell activation profile correlated with the concentration of IL-5 in serum and bronchoalveolar lavage fluids (10, 11, 51). More controversial are studies on the relative importance of mast cells as cytokine-producing cells with eosinophilia-regulating capabilities. Although mast cells have been shown to produce and contain preformed stores of IL-4 and IL-5, and IgE-dependent activation results in the secretion of these eosinophil-regulating factors, mast cell-deficient mice do not show any defect in allergen-induced eosinophil recruitment (52, 53). These data indicate that mast cells are of limited importance as a cellular source of IL-5 in the regulation of allergen-induced eosinophil accumulation in inflamed tissues. Besides T cells and mast cells, eosinophils themselves have been shown to produce IL-5. However, the current view about eosinophil-derived IL-5 is that this cytokine acts predominantly as an autocrine survival factor within the tissue. In fact, we were not able to detect IL-5-producing eosinophils in our analysis of cytokine-producing cells obtained from peritoneal lavage fluids of allergen-sensitized and -challenged mice. This might be due to the sensitivity of the method used to detect intracellular cytokines, but this result suggests that the amount of IL-5 produced by eosinophils appears to be considerably lower compared with T cells and NK cells.
More recently, H. Warren et al. have demonstrated IL-5 production by
human NK cells in vitro (25, 26). In their studies, purified peripheral
blood NK cells were analyzed for their capacity to produce IL-5 and
IFN- following stimulation with IL-2 in primary and secondary
cultures. The production of IL-5 was IL-2 dependent and required the
presence of accessory cells or NK-specific target cells. Moreover, the
secretion of IL-5 and IFN- was affected profoundly by the addition
of IL-4, IL-12, IL-10, and IL-15 and unrelated to the cytolytic
function of these cells. We have confirmed and extended these
observations and demonstrated the existence of distinct IL-5 high and
low producing NK cell clones producing a differential cytokine pattern
(unpublished observation). Moreover, the polarized cytokine profile of
both IL-5 high and low producing NK cell subsets was found to be stable
over time and most likely determined by exposure to specific cytokines
during initial activation events. This was demonstrated in experiments
in which NK cells cultured in the presence of IL-12 lost their ability
to produce IL-5 in response to IL-2, despite producing similar levels
of IFN- in parallel cultures without IL-12. Thus, the cytokine
environment present at the beginning of an inflammatory response may
induce the production of a polarized cytokine pattern in NK cells,
which, similar to the well-known Th1 and Th2 cell types, may influence
the outcome of a specific immune response. The present study further
extends these observations by demonstrating first an increased
infiltration of NK cells in response to allergen exposure of sensitized
mice, and second, IL-5 production by these NK cells in vivo. The
allergen-induced increase in the total number as well as number of
IL-5-producing NK cells was comparable with the results obtained with T
cells, although the absolute values were about 10 times lower for NK
cells. Nevertheless, these results suggest that significant amounts of
the IL-5 detectable at the site of inflammation are derived from NK
cells. However, conclusions about the relative contribution of T cells
and NK cells to the overall IL-5 production are difficult, because
cytokine-producing cells were only analyzed at a single point in time.
Therefore, we cannot exclude the possibility that kinetic differences
in the cytokine production profile between T cells and NK cells
following Ag provocation may differentially affect the levels of IL-5
as well as the number of infiltrating eosinophils. On the other hand,
the results obtained with NK cell-depleted mice, demonstrating a
reduction of the IL-5 levels of more than 50%, rather suggest a higher
contribution of NK cells to the total amount of IL-5 produced than
would be expected from the total number of cytokine-producing cells.
We cannot exclude the possibility that depletion of NK cells by NK1.1
Abs has additional effects, such as changes in the overall cell-cell
communication network as well as depletion of additional,
IL-5-producing cell types. Indeed, it recently has been demonstrated
that a small subpopulation of T cells bearing the NK1.1 Ag rapidly
produces IL-4, IL-5, and IFN- after in vivo activation via the
CD3/TCR complex (41, 42). These observations suggest that these cells
may provide the initial source of IL-4 required for the priming of
CD4+ T cells to develop into a Th2 cell phenotype, as well
as for the initiation of IgE production by B cells (47, 48).
Consequently, one might expect that treatment of mice with
anti-NK1.1 Abs, which not only deplete NK cells, but also those
specific NK1.1-bearing T cell subsets, would prevent the
development of Th2 cells and reduce the production of the Th2
cell-derived cytokines IL-4 and IL-5, as well as the synthesis of
allergen-specific IgE. Our results, however, clearly demonstrate that
treatment of mice with anti-NK1.1. Abs almost completely eliminated
NK cells within the pertioneal cavity, whereas the numbers of
NK1.1.-expressing CD3-positive T cells were reduced by only 50%.
Similarly, the number of IL-5-producing T cells bearing the NK1.1. Ag
was 5- to 10-fold lower compared with the number of IL-5-producing NK
cells. Moreover, treatment of mice with anti-NK1.1 Abs either
before the allergen challenge or during the immunization and challenge
procedure resulted in comparable suppression of eosinophil infiltration
and cytokine production, with no overall change of the Th2 cell
cytokine pattern, suggesting that treatment with NK1.1 Abs during the
immunization did not alter the development of Ag-specific Th2 cells nor
the production of IgE. Furthermore, no significant changes were found
in the number of infiltrating and cytokine-producing T cells,
suggesting no T cell inhibitory effect through the administration of
NK1.1. Abs. Taken together, these data clearly indicate that, at least
in our model, NK1.1.-bearing T cells are of limited importance in the
regulation of eosinophilia, eosinophil infiltration, and IL-5
production.
In conclusion, the data presented in this study clearly demonstrate
that NK cells are capable of IL-5 production in vivo, and thereby
contribute to the development of an eosinophilic inflammatory response.
These results, together with our recent data with NK cell clones
demonstrating clear differences in signal requirement for the induction
of IL-5 and IFN- production and the existence of distinct IL-5 high
and low producing NK cell clones, suggest that cytokines available in
the local environment profoundly affect the range of cytokines produced
by activated NK cells. As a consequence, one set of cytokines released
by NK cells may favor the development of a characteristic Th1-type
immune response, whereas other cytokines such as IL-5 may contribute to
eosinophilic inflammations, as found in patients with asthma or
parasitic infections.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christoph Walker, Novartis Horsham Research Centre, Department of Respiratory Diseases, Wimblehurst Road, Horsham, West Sussex RH12 4AB U.K. E-mail address:
Received for publication June 18, 1997. Accepted for publication April 14, 1998.
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References |
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 M. J. Loza, L. Zamai, L. Azzoni, E. Rosati, and B. Perussia Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells Blood, February 15, 2002; 99(4): 1273 - 1281. [Abstract] [Full Text] [PDF]
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 J. R. Crosby, H. H. Shen, M. T. Borchers, J. P. Justice, T. Ansay, J. J. Lee, and N. A. Lee Ectopic expression of IL-5 identifies an additional CD4+ T cell mechanism of airway eosinophil recruitment Am J Physiol Lung Cell Mol Physiol, January 1, 2002; 282(1): L99 - L108. [Abstract] [Full Text] [PDF]
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 S.D. Message and S.L. Johnston The immunology of virus infection in asthma Eur. Respir. J., December 1, 2001; 18(6): 1013 - 1025. [Abstract] [Full Text] [PDF]
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J. G. Ford, D. Rennick, D. D. Donaldson, R. Venkayya, C. McArthur, E. Hansell, V. P. Kurup, M. Warnock, and G. Grunig IL-13 and IFN-{gamma}: Interactions in Lung Inflammation J. Immunol., August 1, 2001; 167(3): 1769 - 1777. [Abstract] [Full Text] [PDF]
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 N. Krug, V. J. Erpenbeck, K. Balke, J. Petschallies, T. Tschernig, J. M. Hohlfeld, and H. Fabel Cytokine Profile of Bronchoalveolar Lavage-Derived CD4+, CD8+, and gamma delta T Cells in People with Asthma after Segmental Allergen Challenge Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 125 - 131. [Abstract] [Full Text] [PDF]
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E. Lach-Trifilieff, R. A. McKay, B. P. Monia, J. G. Karras, and C. Walker In Vitro and In Vivo Inhibition of Interleukin (IL)-5-Mediated Eosinopoiesis by Murine IL-5R{alpha} Antisense Oligonucleotide Am. J. Respir. Cell Mol. Biol., February 1, 2001; 24(2): 116 - 122. [Abstract] [Full Text]
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T. Hussell and P. J. M. Openshaw IL-12-Activated NK Cells Reduce Lung Eosinophilia to the Attachment Protein of Respiratory Syncytial Virus But Do Not Enhance the Severity of Illness in CD8 T Cell-Immunodeficient Conditions J. Immunol., December 15, 2000; 165(12): 7109 - 7115. [Abstract] [Full Text] [PDF]
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B. R. Lauwerys, N. Garot, J.-C. Renauld, and F. A. Houssiau Cytokine Production and Killer Activity of NK/T-NK Cells Derived with IL-2, IL-15, or the Combination of IL-12 and IL-18 J. Immunol., August 15, 2000; 165(4): 1847 - 1853. [Abstract] [Full Text] [PDF]
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J. S. Wild, A. Sigounas, N. Sur, M. S. Siddiqui, R. Alam, M. Kurimoto, and S. Sur IFN-{gamma}-Inducing Factor (IL-18) Increases Allergic Sensitization, Serum IgE, Th2 Cytokines, and Airway Eosinophilia in a Mouse Model of Allergic Asthma J. Immunol., March 1, 2000; 164(5): 2701 - 2710. [Abstract] [Full Text] [PDF]
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S.-i. Kagami, H. Nakajima, K. Kumano, K. Suzuki, A. Suto, K. Imada, H. W. Davey, Y. Saito, K. Takatsu, W. J. Leonard, et al. Both Stat5a and Stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue Blood, February 15, 2000; 95(4): 1370 - 1377. [Abstract] [Full Text] [PDF]
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 Y. Zhang and E. Y. Denkers Protective Role for Interleukin-5 during Chronic Toxoplasma gondii Infection Infect. Immun., September 1, 1999; 67(9): 4383 - 4392. [Abstract] [Full Text] [PDF]
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 M. Korsgren, C. G.A. Persson, F. Sundler, T. Bjerke, T. Hansson, B. J. Chambers, S. Hong, L. Van Kaer, H.-G. Ljunggren, and O. Korsgren Natural Killer Cells Determine Development of Allergen-induced Eosinophilic Airway Inflammation in Mice J. Exp. Med., February 1, 1999; 189(3): 553 - 562. [Abstract] [Full Text] [PDF]
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D. Peritt, S. Robertson, G. Gri, L. Showe, M. Aste-Amezaga, and G. Trinchieri Cutting Edge: Differentiation of Human NK Cells into NK1 and NK2 Subsets J. Immunol., December 1, 1998; 161(11): 5821 - 5824. [Abstract] [Full Text] [PDF]
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