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*
Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304; and
Schering Plough Research Institute, Schering Plough Corporation, Lafayette, NJ 07848
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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for its initial development. As CD4+ T
cells from IL-10-/- mice will cause colitis when
transferred into recombinase-activating gene (Rag)-deficient
recipients, we considered the possibility that the recipients’ NK
cells could be an important source of IFN- for the development of
colitis. Therefore, the ability of IL-10-/-
CD4+ T cells to cause colitis in Rag-deficient recipients
that had been depleted of NK cells was tested. Contrary to our
expectations, NK cell-depleted recipients of IL-10-/-
CD4+ T cells developed accelerated disease compared with
nondepleted recipients. Furthermore, CD4+ T cells from
normal mice (IL-10+/+) also caused colitis in NK
cell-depleted recipient mice, but not in nondepleted recipients. NK
cells inhibited effector CD4+CD45RBhigh T
cells, and subsequent experiments showed that this effect was dependent
on perforin. Thus NK cells can play an important role in
down-regulating Th1-mediated colitis by controlling the responses of
effector T cells to gut bacteria. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-chain-deficient, and Gi-deficient mice (8, 9, 10, 11, 12, 13).
Additional murine models of chronic intestinal disease have been
generated by disrupting the balance between pro- and
anti-inflammatory elements either by chemical insult
(14) or by the reconstitution of immunodeficient mice with
subsets of CD4+ T cells (15, 16, 17). All of these
models are being studied in an effort to identify the pathogenic
mechanisms responsible for initiating and/or sustaining human
IBD.
Th1 cells are primary mediators of intestinal disease in the majority
of these IBD models (10, 14, 18, 19). Although it is well
established that Th1 T cells provide protection against bacterial and
parasitic infections (reviewed in Refs. 20 and
21), there is now evidence that the uncontrolled
generation and/or activation of Th1 cells may underlie the
immunopathologic changes seen in a variety of models of chronic
inflammation (i.e., colitis, thyroiditis, pancreatitis, nephritis, and
experimental allergic encephalitis). Given the potential of Th1 cells
to play either a protective or pathogenic role, we have previously
investigated the role of IFN- in the development and maintenance of
the colitis seen in IL-10-/- mice. Treatment of neonatal
IL-10-/- mice with anti-IFN- mAb dramatically
delayed the onset and reduced the severity of colonic inflammation.
However, anti-IFN- mAb treatment of IL-10-/-
adults had no effect on their established disease (19, 22, 23). Therefore, we concluded that IFN- is a critical
component required for initiating, but not for sustaining,
CD4+ Th1-dependent colitis in IL-10-/- mice.
This conclusion is consistent with the ability of anti-IFN- mAb
treatment to prevent the development of colitis in a CD4+ T
cell transfer model (24).
Given the importance of IFN- during the inductive phase of a
pathogenic Th1 response in IL-10-/- mice, we questioned
whether NK cells are a primary source of this early IFN- production.
In other experimental models, NK cells have been shown to be involved
in the differentiation of naive CD4+ T cells into Th1 cells
(25). Infectious organisms, such as Listeria
monocytogenes and Toxoplasma gondii, are capable of
stimulating macrophages and/or dendritic cells to secrete IL-12 and
TNF-, which in turn induce NK cells to produce IFN- (26, 27). This production of IFN- by NK cells early in the immune
response is critical for the induction of a rapid healing Th1 response
to several different infectious organisms, including Leishmania
major, T. gondii, L. monocytogenes, and
murine cytomegalovirus (28, 29, 30, 31, 32, 33, 34). Moreover, in vitro
studies have shown that IL-10 is a potent suppresser of IFN-
production by NK cells because it inhibits the ability of accessory
cells to produce the factors necessary for NK cell activation
(35, 36). Therefore, as it seemed likely that the
dysregulated interactions of NK cells and accessory cells may serve to
initiate the development of Th1-mediated colitis in
IL-10-/- mice, we tested the possibility that NK cells
were a contributing factor to Th1-mediated colitis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6 (B6) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) or from Taconic Farms, (Germantown, NY). Recombinase-activating gene 1-deficient/C57BL/6 (Rag1-/-) mice were either from The Jackson Laboratory or from a colony maintained at the DNAX Animal Care Facility. Pore-forming-protein/Rag2-deficient (pfp-/-/Rag2-/-) B6/129 outbred mice were obtained from Taconic Farms; B6/129 outbred mice were generated at the DNAX Animal Care Facility. The immunodeficient mice were housed in micro isolator cages in a specific pathogen-free facility and were given only sterile bedding, food, and water. Immunocompetent mice were kept in conventional housing.
Antibodies
Both the PK136 clone (anti-NK1.1) and the L243 clone
(anti-human MHC class II; isotype control) were obtained from
American Type Culture Collection (Manassas, VA). Ascites was made from
each of these clones at Harlan Bioproducts for Science (Madison, WI)
and tested for endotoxin. Mice were given 2 mg of Ig from saturated
ammonium sulfate (SAS) cut PK136 i.p., followed by weekly i.p.
injections of 1 mg. The isotype control mice were given 0.5 to 0.8 mg
of SAS cut L243 i.p. at all time points. The
anti-asialo-GM1 Ab (Wako Chemicals, Richmond, VA) was
reconstituted according to the manufacturer’s specifications, and 50
µl was given i.p. on a weekly basis. All depleting or control Abs
were given to the mice the day before cell transfer, and then every 6
to 8 days for the duration of the experiment. Efficacy of the in vivo
depleting Ab was determined by flow cytometric analysis of the spleens
of treated mice. After RBC lysis, spleen cells of treated mice were
stained with anti-CD4 FITC (Caltag, Burlingame, CA), anti-NK1.1
PE (PharMingen, San Diego, CA) and, as a separate NK cell marker,
biotinylated DX5 (PharMingen), followed by streptavidin-PE (Caltag),
and analyzed by flow cytometry (see Fig. 1
).
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CD4+ splenic T cells were obtained by two separate
methods, depending on the experiment. In the first method (see Tables I
and II; Fig. 2), spleens were first enriched for CD4+ T
cells by red cell lysis and magnetic bead depletion using
lineage-specific mAb supernatants (10% v/v): B220 (B cells)
and Ter119 (erythrocytes). mAb-stained cells were removed in a magnetic
field using goat anti-rat IgG (Fc) and goat anti-rat IgG
(H + L)-coated magnetic beads (PerSeptive Diagnostics,
Cambridge, MA). Remaining cells were then stained with
anti-CD4-FITC and anti-NK1.1 PE or with anti-CD4-PE
(Caltag) and anti-CD45RB-FITC (PharMingen) for cell sorting.
Two-color cell sorting was performed using a FACStarPlus
(Becton Dickinson, Mountain View, CA); the sorted
CD4+NK1.1-,
CD4+CD45RBlow, and
CD4+CD45RBhigh T cells were >98% pure upon
reanalysis. Alternatively (see Fig. 4), splenic cells were stained
after RBC lysis successively with anti-CD4 biotin (PharMingen),
streptavidin-FITC (Biomedia, Foster City, CA), and magnetic cell
separation system (MACS) biotin microbeads (Miltenyi Biotec, Auburn,
CA). The cells were then run over successive MACS VS+
columns until a purity of >95% was obtained by flow cytometric
analysis. Purified CD4+ cells (1 x 105)
were injected i.p. into Rag1-/- or
pfp-/-/Rag2-/- recipient mice. From 4 to 6
wk after T cell transfer, mice were sacrificed and analyzed for the
presence of enterocolitis.
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Microscopic examination of mouse large intestine was performed in a blinded fashion by the same pathologist (M. W. Leach) on formalin-fixed tissue sections stained with hematoxylin and eosin, as previously described (19). As the lesions in IL-10-/- mice can be multifocal, longitudinal sections of the entire length of the colon were evaluated, taking into account both the number of lesions and their severity. Each region of the colon (cecum; ascending, transverse, and descending colon; and rectum) was graded semiquantitatively as 0 (no change) to 5 (most severe change). The grading represents an increasing incidence and severity of transmural inflammation, goblet cell loss, crypt abscesses and ulceration, and fibrosis in the lamina propria. The summation of the score for each segment of the colon provides a total disease score per mouse (0–25) where: 0 indicates no change; 1 to 5, mild disease; 6 to 10, mild-moderate; and 11 to 20, severe. No mice in these studies had a score above 20 because such severe disease results in death.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To determine if early IFN- production by NK cells was important
for the development of the pathogenic CD4+ T cells, we used
a CD4+ T cell transfer model. We have previously shown that
purified CD4+ T cells from IL-10-/- mice will
cause colitis when transferred into immunodeficient mice (8, 37). To determine if the colitis that develops in
immunodeficient recipients depended on the presence of
IFN--producing host NK cells, we transferred IL-10-/-
CD4+ T cells into NK cell-depleted immunodeficient mice. NK
cell-depleted recipient mice were created by treating
Rag1-/- (B6) mice with the anti-NK1.1 mAb PK136 in
vivo. The ability of PK136 to deplete NK cells in B6 mice has been well
documented (38). Flow cytometric analysis of spleens from
anti-NK1.1-treated Rag1-/- mice showed at least 80 to
90% depletion of NK cells (Fig. 1
).
Purified splenic CD4+ T cells from IL-10-/-
mice were injected into anti-NK1.1-treated or isotype
control-treated Rag1-/- mice. Importantly, the
IL-10-/- CD4+ T cells that were transferred
did not contain the rare NK1.1+ CD4+ T cell
subset (see Materials and Methods) and, thus, any
differences seen in anti-NK1.1-treated recipients were due to the
elimination of NK cells rather than NK1.1+ T cells. Results
from previous experiments have shown that colitis develops in
Rag2-/- recipients 6 to 8 wk after the transfer of
IL-10-/- CD4+ T cells (8, 37).
In this case, however, the experiment was terminated early because the
NK cell-depleted Rag1-/- recipients were moribund by 4 wk
after cell transfer. Histological analysis confirmed our gross
observations that the NK cell-depleted recipients of
IL-10-/- CD4+ T cells had developed moderate
to severe colitis, whereas only mild colitis was found in the isotype
control-treated recipients at this time point (Table I). The colitis was characterized by
epithelial hyperplasia, which resulted in crypt hypertrophy,
mucin depletion from goblet cells, and inflammatory cell infiltrates,
which consisted of mononuclear cells accompanied by smaller numbers of
neutrophils and rare eosinophils (data not shown, but see below).
Furthermore, increased disease severity correlated with a higher number
of donor ßTCR+ CD4+ T cells found by flow
cytometric analysis of the spleens of anti-NK1.1-treated (average
of 1.5 x 106 CD4+ T cells/spleen) vs
isotype control-treated recipients (average of 0.6 x
106 CD4+ T cells/spleen). Therefore, our
findings suggested that the absence of NK cells actually augmented the
ability of IL-10-/- CD4+ T cells to cause
inflammation in the colon.
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Our previous studies with IL-10-/- mice have shown
that they develop colitis because an important regulatory subpopulation
of CD4+ T cells is either absent or dysfunctional due to
their inability to produce IL-10 (22, 37). Hence the
inhibitory effect of NK cells on the development of colitis may be
detectable only during the transfer of an IL-10-deficient
CD4+ T cell population. This implies that a WT,
IL-10-producing, CD4+ T cell population would not cause
colitis in NK cell-deficient recipient mice. To test this, we
transferred purified splenic CD4+ T cells from WT C57BL/6
mice into anti-NK1.1-treated or into isotype control-treated
Rag1-/- recipients. As shown in Figure 2, 80% of anti-NK1.1-treated
Rag1-/- recipients of WT CD4+ T cells
developed colitis within 4 to 6 wk after transfer. The colitis in the
anti-NK1.1-treated recipients of WT CD4+ T cells (Fig. 3D) was morphologically
similar to that seen in anti-NK1.1-treated recipients of
IL-10-/- CD4+ T cells. The transfer of low
numbers of CD4+ T cells into immunodeficient mice has been
shown by others to result in the development of colitis 3 to 6 mo after
the T cell transfer (17, 39, 40). In our studies, however,
WT CD4+ T cells only rarely induced colitis in isotype
control-treated Rag1-/- mice 4 to 6 wk after transfer
(Figs. 2 and 3C). These results indicate that NK cells can
play an important regulatory role in the prevention of colitis in
immunodeficient recipients irrespective of the source of the
transferred CD4+ T cell population.
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production from NK cells in vitro (41). Therefore,
anti-NK1.1 mAb treatment in vivo may cause NK cells to release
IFN- before their depletion. To investigate this possibility,
Rag1-/- recipient mice were also depleted of NK cells
using anti-asialo GM1 (anti-ASGM1) Ab, which has
been shown to deplete NK cells in vivo but does not activate NK cells
(38). The transfer of 1 x 105 WT
CD4+ T cells into ASGM1-treated Rag1-/-
recipients resulted in colitis of equivalent incidence and severity as
that seen in anti-NK1.1-treated recipients (Fig. 2). Importantly,
NK cell-depleted Rag1-/- mice that did not receive T
cells did not develop colitis and remained healthy throughout the
experimental time period (Figs. 2 and 3). This control shows that NK
cell depletion in and of itself does not result in colonic inflammation
in immunodeficient mice. CD4+CD45RBlow regulatory T cells engraft normally in NK cell-depleted Rag1-/- mice
The transfer of WT CD4+ T cells into syngeneic Rag-deficient or SCID mice generally leads to reconstitution without signs of a pathogenic response in the gastrointestinal tract (15, 16). Recently, it was demonstrated that this outcome is dependent on the simultaneous engraftment of effector and regulatory CD4+ T cells, which express high and low levels of the CD45RB molecule, respectively. Purified effector CD4+CD45RBhigh (RBhigh) T cells caused colitis upon transfer into immunodeficient recipients unless cotransferred with CD4+CD45RBlow (RBlow) T cells, which are enriched for regulatory T cells (15, 16, 18). Our finding that unseparated WT CD4+ T cells caused an unusually high incidence of colitis in NK cell-depleted Rag1-/- recipients suggested that NK cells were somehow necessary to insure a balanced reconstitution by effector and regulatory CD4+ T cell populations.
We hypothesized that NK cells could prevent colitis in recipients of WT
CD4+ T cells either by inhibiting the generation of
effector RBhigh T cells or by aiding in the establishment
of regulatory RBlow T cells. To determine if NK cells were
necessary for the establishment of regulatory T cells, WT
RBlow T cells were transferred into NK cell-depleted or NK
cell-containing Rag1-/- mice. These same recipients were
then transplanted with RBhigh T cells 21 days later. By
allowing the RBlow T cells 3 wk to expand and home to the
relevant tissues, we hoped to create recipient mice that had an
established regulatory T cell population before transferring in the
effector RBhigh T cells. Treatment with anti-NK1.1 or
isotype control mAb was initiated either at day -1 (i.e., before the
RBlow T cell transfer) or at day 20 (i.e., before the
RBhigh T cell transfer). Recipient mice were sacrificed 6
wk after the RBhigh T cell transfer (see Table II).
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, lines 1 and 2). When
recipients of RBlow T cells that were depleted of NK cells
just prior to receiving RBhigh T cells, four out of five
did not develop colitis (Table II, line 3). This result suggests that
the presence of NK cells is unnecessary for the ability of an
established regulatory T cell population to control effector T cells.
Importantly, RBlow cells that had been transferred directly
into anti-NK1.1-treated recipients were capable of preventing
colitis by the RBhigh subset (Table II, line 4). These
results show that NK cells are not necessary for the establishment of
functional RBlow T cells and, thus, suggest that NK cells
must be affecting RBhigh T cells. Therefore, we conclude
that when unfractionated CD4+ T cells are transferred into
immunodeficient recipients, in which no established regulatory T cell
population exists, NK cells are required for the control of effector T
cell responses to enteric bacteria. The inhibitory role of NK cells in colitis is perforin dependent
The ability of NK cells to inhibit effector T cells is contrary to
the characterization of NK cells as promoters of Th1-mediated
inflammatory responses. However, our data are supported by increasing
evidence that NK cells may play a regulatory role in some Th1-mediated
immune responses, such as pneumonitis, autoimmunity in lpr
mice, and experimental allergic encephalitis in B6 mice
(42, 43, 44). The mechanisms for this inhibitory effect of NK
cells on Th1-mediated responses are currently unknown. Activated NK
cells can secrete TGF-ß (45), and TGF-ß has been
implicated in the prevention of colitis in several models (12, 13, 46). NK cells also secrete TNF-, which can have cytotoxic
effects on activated T cells (47). However, NK cells are
best characterized by their ability to lyse target cells in a
perforin-dependent manner. NK cells from mice that are deficient in
perforin (pfp-/- mice) are unable to lyse allogeneic,
virally infected, or NK cell-sensitive targets (48).
Therefore, we considered the possibility that NK cells might be lysing
effector T cells by a perforin-dependent mechanism to prevent the
induction of colitis in our T cell transfer system.
To test the role of perforin in our model of colitis, we transferred
CD4+ T cells into immunodeficient mice that were also
deficient in perforin (pfp-/-/Rag2-/-
mice). The pfp-/-/Rag2-/- mice contain no T
or B cells and their NK cells are unable to lyse targets by a
perforin-mediated mechanism. As a positive control, some recipients
were physically depleted of NK cells by anti-ASGM1 Ab treatment
prior to T cell transfer. As shown in Figure 4, 67% of NK cell-depleted
pfp-/-/Rag-/- recipients developed mild to
moderate colitis by 4 wk after T cell transfer. The mild colitis
observed in these pfp-/-/Rag2-/- recipients
as opposed to Rag1-/- recipients (Fig. 4 vs Fig. 2) is
most likely due to the differences in genetic background (see
Materials and Methods) (19). In comparison,
pfp-/-/Rag2-/- recipients of
CD4+ T cells developed colitis with the same incidence and
severity as in their NK cell-depleted counterparts (Fig. 4). As there
was no significant difference between the two groups, we concluded that
NK cells use perforin to regulate the development of colitis in our
CD4+ T cell transfer model. However, NK cells have also
been shown to express Fas ligand (FasL) and to lyse Fas-expressing
target cells (49). Therefore, it is possible that perforin
is not the only mechanism by which NK cells can inhibit effect on
CD4+ T cells, and it will be interesting to determine if
Fas/FasL, as well as TGF-ß, contribute to the ability of NK cells to
inhibit effector T cells.
In summary, we have demonstrated a previously unappreciated role for NK cells as regulators, rather than promoters, of Th1-mediated colitis in a CD4+ T cell transfer system. Furthermore, we have been able to characterize this regulatory effect as being directed against the effector CD4+CD45RBhigh T cell subset and dependent on perforin. What remains unclear is whether NK cells inhibit effector T cells directly or indirectly. It is possible that NK cells directly lyse activated T cells. Alternatively, it is possible that NK cells control effector T cell activation by eliminating professional APCs, as studies by others have shown that NK cells can lyse B7-1+ macrophages and dendritic cells (50, 51). We are currently performing experiments to differentiate between these two possibilities. Finally, our findings indicate that there is a critical role of NK cells in controlling effector T cell responses. This role is most evident in the absence of an established regulatory CD4+ T cell population. As NK cells are found in the lamina propria of the gut (52) (data not shown), their regulatory effect may be crucial in controlling the extent of local mucosal Th1 cell responses to enteric Ags during the development of regulatory T cell responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Madeline Fort, DNAX Research Institute, 901 California Ave., Palo Alto, CA 94306. E-mail address:
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; IL-10-/-, IL-10-deficient; pfp-/-, pore-forming protein-deficient; Rag1-/- mice, recombinase-activating gene 1-deficient mice; RBhigh, CD4+CD45RBhigh-expressing cells; RBlow, CD4+CD45RBlow-expressing cells; WT, wild-type (IL-10+/+); PE, phycoerythrin; B6 mice, C57BL/6 mice; ASGM1, asialo GM1; FasL, Fas ligand; SAS, saturated ammonium sulfate.
Received for publication April 6, 1998. Accepted for publication May 27, 1998.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183:2391.This article has been cited by other articles:
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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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L. D. Poulton, M. J. Smyth, C. G. Hawke, P. Silveira, D. Shepherd, O. V. Naidenko, D. I. Godfrey, and A. G. Baxter Cytometric and functional analyses of NK and NKT cell deficiencies in NOD mice Int. Immunol., July 1, 2001; 13(7): 887 - 896. [Abstract] [Full Text] [PDF]
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P. G. Andres, P. L. Beck, E. Mizoguchi, A. Mizoguchi, A. K. Bhan, T. Dawson, W. A. Kuziel, N. Maeda, R. P. MacDermott, D. K. Podolsky, et al. Mice with a Selective Deletion of the CC Chemokine Receptors 5 or 2 Are Protected from Dextran Sodium Sulfate-Mediated Colitis: Lack of CC Chemokine Receptor 5 Expression Results in a NK1.1+ Lymphocyte-Associated Th2-Type Immune Response in the Intestine J. Immunol., June 15, 2000; 164(12): 6303 - 6312. [Abstract] [Full Text] [PDF]
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Y. Suzuki, A. Sher, G. Yap, D. Park, L. E. Neyer, O. Liesenfeld, M. Fort, H. Kang, and E. Gufwoli IL-10 Is Required for Prevention of Necrosis in the Small Intestine and Mortality in Both Genetically Resistant BALB/c and Susceptible C57BL/6 Mice Following Peroral Infection with Toxoplasma gondii J. Immunol., May 15, 2000; 164(10): 5375 - 5382. [Abstract] [Full Text] [PDF]
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 D. Haller, S. Blum, C. Bode, W. P. Hammes, and E. J. Schiffrin Activation of Human Peripheral Blood Mononuclear Cells by Nonpathogenic Bacteria In Vitro: Evidence of NK Cells as Primary Targets Infect. Immun., February 1, 2000; 68(2): 752 - 759. [Abstract] [Full Text] [PDF]
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 K. Arase, K. Saijo, H. Watanabe, A. Konn |
