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*
Department of Internal Medicine, Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, and Veterans Affairs Medical Center, Cincinnati, OH 45220; and
Department of Immunology and Microbiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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gene expression but decreased CD4+ T
cell activation and decreased or delayed T cell production of other
cytokines. We examined the possibilities that IL-4 stimulation of
IFN- production, suppression of IL-1 or IL-2 production, or
induction of TNF-
or Fas-mediated apoptosis could account for
IL-4’s suppressive effect. The suppressive effect of IL-4 was not
reversed by IL-1, IL-2, or anti-TNF- or anti-IFN- mAb
treatment, or mimicked by treatment with anti-IL-2R (CD25) and
anti-IL-2Rß (CD122) mAbs. Early IL-4 treatment failed to inhibit
anti-IgD-induced Ab production in Fas-defective lpr
mice; however, the poor responsiveness of lpr mice to
anti-IgD made this result difficult to interpret. These
observations indicate that exposure to IL-4, while T cells are first
being activated by Ag presentation, can inhibit T cells activation or
promote deletion of responding CD4+ T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The experiments described in this paper were performed to determine whether altering the timing of lymphocyte stimulation by IL-4 during the course of a response to anti-IgD Ab would modify that response. In particular, we were influenced by cell transfer studies that suggest that the lag between mIgD cross-linking-induced B cell activation and the activation of helper T cells in this system results in the death of most activated B cells before they can be "rescued" by T cell help (11). Because costimulation with IL-4 can increase the proliferative response and prolong the survival of B cells that have had their mIg cross-linked (12), we hypothesized that IL-4 treatment, starting simultaneously with injection of anti-IgD Ab, would considerably enhance the Ab response to anti-IgD Ab. We have found instead that such treatment suppresses T cell activation and cytokine production as well as Ab responses in this system.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice were purchased from the Small Animals Division of the National Cancer Institute (Frederick, MD). Male C57BL/6J and C57BL/6.lpr mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were used at 7–12 wk of age.
Cytokines
Murine rIL-4 was a gift of Dr. Robert Coffman (DNAX Research Institute, Palo Alto, CA). Human rIL-2 and human rIL-1ß (IL-1) were gifts of Dr. Richard Chizzonite (Hoffmann-LaRoche, Nutley, NJ).
Antibodies
The following Abs were produced and tested for specificity as
previously described: affinity-purified goat Ab specific for mouse IgD
(GM
) (13), affinity-purified rabbit anti-mouse
IgE (14), affinity-purified goat anti-rabbit IgG that
was absorbed with mouse IgG (a gift of Dr. Ellen Vitetta, University of
Texas Health Science Center, Dallas, TX) (15), goat IgG,
rat IgG2b anti-mouse FcRII mAb (24G2) (16), rat
IgG2a anti-mouse IgE mAb (EM95) (17), mouse IgG1
anti-FITC mAb (CG5) (produced in our laboratory by Dr. Diana
Goroff), rat IgG2b anti-IL-4 mAb (BVD4-1D11.2) (18),
rat IgG1 anti-IL-4 mAb (BVD6-24G2.3) (19), rat IgG1
anti-IFN- mAb (XMG-6) (20, 21), mouse IgM
anti-CD25 mAb (7D4) (22, 23), rat IgG1 anti-CD25
mAb (PC-61) (24), rat IgG2b anti-CD4 mAb (GK1.5)
(25), rat IgG1 anti-CD122 mAb (TMB1)
(26), mouse IgG2ab
anti-IgDa mAb (FF1-4D5) (27),
mouse IgG2bb anti-IgDa
mAb (Ha/1) (28), rat IgG1
anti-TNF- mAb (MP6-XT22) (18), and two isotype
control mAbs, rat IgG2b anti-NP (J1.2) and rat IgG1 anti-ß
galactosidase mAb (GL113) (gifts of John Abrams, DNAX, Palo Alto, CA).
Purified mouse IgG anti-human IL-2 mAb (5B1) was a gift of Dr.
Richard Chizzonite (Hoffmann-LaRoche). Rabbit anti-mouse IgG1 Abs
were produced and affinity purified (7). Some Abs were
conjugated with alkaline phosphatase, FITC, or biotin as previously
described (4, 15, 29).
Ab assays
GM-treated mice were bled at times that peak serum IgE and
IgG1 levels are normally found (7, 30, 31). Serum IgG1 was
quantitated by radial immunodiffusion with RM1 antisera (The
Binding Site, San Diego, CA) (11). Purified mAb CG5 was
used as a standard for mouse IgG1. Serum IgE concentration was
determined by ELISA (30). Serum IgG1 anti-goat IgG
titers were determined by ELISA (32).
Enzyme-linked immunospot (ELISPOT) assay
The frequency of IL-4-producing cells was determined by an ELISPOT assay performed as previously described (33), with the exceptions that wells were coated with the anti-IL-4 mAb, BVD4-1D11.2, (10 µg/ml in PBS), bound IL-4 was detected with biotin-labeled BVD6-24G2.3 (4 µg/ml), and murine rIL-4 was used as a positive control.
Preparation of cytokine-anti-cytokine Ab complexes
IL-2 or IL-4, at a concentration of 200–1000 µg/ml, was mixed at a 2:1 molar ratio with neutralizing anti-IL-2 or anti-IL-4 mAb, respectively, which were at an initial concentration of 10 to 40 mg/ml, to prepare complexes. These complexes greatly extend the in vivo half-life of the cytokines (34). After 2 min at room temperature, complexes were diluted with normal saline to the concentration at which they would be injected into mice. Complexes were always freshly prepared before use.
Immunofluorescence staining
Spleen cell preparations were prepared and depleted of
erythrocytes. Two million cells in 100 µl of HBSS supplemented with
10% newborn bovine serum and 0.2% NaN3 (HNA)
were stained on ice for 30 min with no Ab (control) or with 1 µg of
fluorescein- or biotin-labeled Abs in the presence of 1 µg of 24G2,
to inhibit binding of reagents to FcRII, then washed 2 times with
HNA. Biotin-labeled cells were incubated with ImmunoSelect
streptavidin-R-PE (Life Technologies, Gaithersburg, MD) by the same
procedure. After staining, cells were washed once with HNA and once
with HBSS plus 0.2% NaN3, then fixed in 2%
paraformaldehyde in PBS. One hundred thousand stained cells were
analyzed for fluorescein- or PE-associated fluorescence, or both, with
a Becton Dickinson FACScan (Becton Dickinson, Mountain View, CA), using
linear or log amplifiers and scatter gates chosen to select small to
medium-sized lymphocytes. Percentages of specifically stained cells and
median fluorescence intensity (MFI) of the cells was calculated with
the Cellquest program (Becton Dickinson, Mountain View, CA).
Isolation and purification of RNA
Cytokine gene expression was evaluated 1, 2, 3, 4, 5, 7,and 10
days after GM injection. Spleens were homogenized in RNAzol
(Tel-Test, Friendswood, TX) with a Polytron PT3000 (Brinkmann
Instruments, Westbury, NY). Total RNA was isolated and quantitated as
described previously (8). Purified RNA (10 µg) was
electrophoresed on a 1% agarose gel containing ethidium bromide to
check RNA concentration and verify that the RNA was not degraded.
RT-PCR
A coupled RT-PCR was used to quantitate tissue mRNA levels
(8). RNA samples were reverse-transcribed with Superscript
reverse transcriptase (Life Technologies, Grand Island, NY),and
cytokine-specific primers (8, 33) were used to amplify
selected cytokines. For each cDNA product, the optimum number of cycles
for PCR amplification was determined experimentally. Relative
concentrations of IFN-, IL-2, IL-3, IL-9, IL-4, and IL-10 mRNA were
determined. Primers for the "housekeeping gene," hypoxanthine
phosphoribosyltransferase (HPRT), were used in each experiment to
verify that equal amounts of RNA were added in each PCR. All cytokine
values were normalized individually to the corresponding hypoxanthine
phosphoribosyltransferase values. Amplified PCR product was detected by
Southern blot analysis (8), and the resulting signal was
quantitated with a PhosphorImager (Molecular Dynamics, Sunnyvale,
CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M-induced serum IgG1 and IgE responses are inhibited by
simultaneous injection of IL-4
To determine whether early stimulation with IL-4 would affect
GM-induced Ab responses, BALB/c mice were left untreated or were
injected with GM or GM and a complex of IL-4 and
anti-IL-4 mAb (IL-4C) that has long-acting IL-4 activity. Mice were
bled 6, 8, and 10 days after the initial injection. IL-4C treatment
inhibited the day 8 IgG1 response by 66% and the IgE response by 87%
(Fig. 1
). Injection of mice with the low
dose of anti-IL-4 mAb used in the IL-4C was insufficient to
suppress IgG1 or IgE responses by itself (Fig. 2). Injection of free IL-4, which has a
short in vivo half-life, at the same dose used in the IL-4C, also had
little effect on serum levels of IgG1 and IgE. Inhibition of IgG1 and
IgE by a single dose of IL-4C was comparable to that caused by
administration of IL-4C on days 0, 2, 4, and 6 (data not shown).
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M-induced IgG1 and IgE responses to the same
extent as complexes that contained 25 µg of IL-4 and 150 µg of
anti-IL-4 mAb (Fig. 3), though
complexes that contained 0.2 µg of IL-4 or less were no longer
capable of inhibiting GM-induced IgG1 and IgE responses (data not
shown). Injection of IL-4C up to 2 days before GM inhibited the
GM-induced IgE response to the same extent as IL-4C injected at
the same time as GM. However, the IgE response was not inhibited
if IL-4C was injected 1 day after GM, and IL-4C injected 2 days
after GM enhanced the IgE response (Fig. 4).
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M-induced T cell activation
Because IL-4 enhances anti-Ig Ab-induced B cell activation, we
suspected that the suppressive effect of IL-4 on GM-induced Ab
responses might result from inhibition of the
CD4+ T cell response to GM. To examine this
possibility, we determined the effects of IL-4C treatment on T cell
IL-2R (CD25) and cytokine expression in GM-treated BALB/c
mice. Mice sacrificed 4 days after GM injection show a
considerable increase in the percentage of splenic
CD4+ T cells that express CD25 and in the extent
of CD25 expression by these cells. These effects of GM were
suppressed by 55–65% by IL-4 (Fig. 5).
IL-4 treatment also modified GM cytokine gene expression.
GM caused considerable increases in IL-2, IL-3, and IL-9 gene
expression by 3 days after injection, and IL-4 and IL-10 gene
expression by 4 days after injection. CD4+ T
cells have previously been shown to be the source of mRNA for these
cytokines (8). Treatment with IL-4C inhibited
GM-induced IL-2, IL-9, and IL-10 responses, and delayed
GM-induced IL-3 and IL-4 responses (Fig. 6). In contrast, IL-4C treatment caused a
large increase in IFN- gene expression that peaked within 1 day of
IL-4C injection and returned over the next 2 days to the levels
observed in mice that had not received IL-4C (Fig. 6).
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M injection; this increase was nearly suppressed to background
levels by IL-4C treatment (Fig. 7). Taken
together with previous evidence that most of the cytokine responses to
GM are CD4+ T cell derived (6, 8), these observations demonstrate that IL-4C treatment at the
time of GM injection has a marked suppressive effect on
CD4+ T cell activation.
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M
injection is not mediated by IFN-
Because IL-4C treatment of GM-injected mice induces a large,
short-lived increase in IFN- gene expression and IFN- can
suppress IgG1 and IgE responses to GM (20), it
seemed possible that IL-4 suppression of the GM-induced immune
response was IFN- mediated. To test this possibility, we examined
whether an anti-IFN- mAb, at a dose that blocks in vivo effects
of endogenously produced IFN- (20), would block IL-4C
inhibition of GM-induced IgE and IgG1 responses. As previously
reported (20), GM-induced IgG1 and IgE responses
were slightly or substantially enhanced, respectively, by injecting
mice with anti-IFN- mAb (Fig. 8).
This mAb, however, only partially blocked IL-4C inhibition of the
GM-induced IgG1 response and had no effect on IL-4C inhibition of
the GM-induced IgE response (Fig. 8). Thus, IL-4C induction of
IFN- production does not account for the inhibitory effects of IL-4
on the response to GM Ab.
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M
injection is not mediated by inhibition of IL-2 production or receptor
expression or inhibition of IL-1 production
IL-4C treatment suppresses IL-2 gene expression (Fig. 6
), and IL-4
has been reported to suppress IL-2R (CD25) and IL-2Rß (CD122)
expression (35). Because IL-2 is an autocrine growth
factor for T cells (36), it seemed possible that
suppression of IL-2 production or IL-2 signal transduction might be
responsible for IL-4 inhibition of GM-induced IgG1 and IgE
responses. To examine these possibilities, we determined whether
treatment of BALB/c mice with mAbs that block the IL-2R (anti-CD25
and CD122 mAbs) would mimic the effect of IL-4 on the Ab response to
GM, and whether treatment with IL-2 (in the form of IL-2C) would
block the ability of IL-4 to inhibit GM-induced Ab production.
Injection of anti-CD25 and CD122 mAbs failed to inhibit IgG1 and
IgE responses to GM (Fig. 9).
Injection of IL-2C 2 days after mice received GM (the time when
IL-2 responses are normally first detected in GM-injected mice;
Ref. 8) enhanced the GM-induced IgG1 and IgE
responses but did not suppress the ability of IL-4 to inhibit these
responses (Fig. 10). Therefore, IL-4
inhibition of IL-2R expression or IL-2 production does not account for
IL-4C inhibition of GM-induced IgG1 or IgE responses. Additional
studies demonstrated that suppression of IL-2 production or signaling
does not account for IL-4C inhibition of GM-induced splenic
cytokine gene expression (data not shown).
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). An additional experiment
demonstrated that the suppressive effect of IL-4 was not reversed when
mice were treated with both IL-1 and IL-2C (data not shown). Thus, it
appears unlikely that IL-4 suppression of endogenous IL-1 production is
responsible for the inhibitory effect of IL-4 on anti-IgD-induced
Ab production.
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M-induced Ab responses is not TNF-
dependent
Activation of memory T cells by anti-CD3 mAb, in the presence
of either IL-2 or IL-4, can stimulate T cell death (39).
Signaling through both the TNFR and Fas have been reported to
contribute to this process (40). To investigate whether
IL-4 suppression of GM-induced Ab production might be mediated by
this process, we examined whether anti-TNF- mAb could block
IL-4-induced suppression and whether IL-4 can suppress GM-induced
Ab responses in lpr mice, which have a defect in Fas
expression (41). Anti-TNF- mAb had little effect on
IL-4 suppression of GM-induced IgG1 and IgE responses (Fig. 12). Attempts to study the role of Fas
in IL-4 suppression of GM-induced Ab responses, however, provided
equivocal results. Fas-deficient mice, even Fas-deficient mice that had
not yet developed detectable lymphadenopathy or serum autoantibodies,
made much smaller IgG1 and IgG1 anti-goat IgG responses to GM
than did wild-type mice, and GM injection failed to increase
serum IgE levels above the high basal levels in these mice (data not
shown). Although IL-4C treatment, which convincingly inhibited
GM-induced IgG1, IgG1 anti-goat IgG, and IgE responses in
wild-type mice, had no effect, or a slight stimulatory effect, on these
responses in Fas-deficient mice, the failure of GM to induce
substantial IgG1 and IgE responses in lpr mice made the lack
of effect of IL-4C difficult to interpret. Our attempts to obtain a
sufficient quantity of a blocking anti-Fas ligand mAb (42, 43) to determine whether acute inhibition of Fas-Fas
ligand interactions would block the inhibitory effects of IL-4C have,
to date, been unsuccessful. Thus, the possibility that IL-4 inhibits
the GM-induced Ab response by inducing Fas-mediated cell death
has neither been established nor eliminated.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The inhibitory effect of accelerated exposure to IL-4 during the immune
response to anti-IgD Ab likely results from an effect of IL-4 on
CD4+ T cell activation. IL-4C treatment
suppresses CD4+ T cell activation, as
demonstrated by inhibition of CD25 expression, cytokine gene
expression, and IL-4 secretion. It is unlikely, however, that IL-4
inhibits CD4+ T cell activation by suppressing
IL-2R expression or IL-2 production. Anti-CD25 and anti-CD122 mAbs
had no effect on anti-IgD-induced Ab responses, and treatment with
IL-2 did not reverse IL-4 inhibition of the Ab response to
anti-IgD. It is also unlikely that IL-4 inhibits GM-induced
CD4+ T cell activation, or deviates the
GM-induced type 2 cytokine response, by stimulating IFN-
production. Although IL-4C treatment does stimulate substantial IFN-
gene expression (possibly by activating CD8+ T
cells to produce this cytokine, as was observed in mice infected with
Schistosoma mansoni; Ref. 45), neutralization
of IFN- does not block the ability of IL-4 to inhibit
GM-induced IgE production. IL-4 suppression of inflammatory
responses that might potentially costimulate T cell activation is
another potential mechanism of IL-4 suppression of anti-IgD-induced
Ab production that has been ruled out by our studies: treatment with
IL-1, at a dose known to enhance T cell-dependent Ab responses
(46) did not reverse the inhibitory effects of
IL-4.
Our observations leave open the possibility that exposure to IL-4
at the time of initial Ag presentation to T cells inhibits T cell
activation or causes the T cells to die by a Fas-mediated process.
Lenardo has demonstrated that exposure of memory T cells to IL-2 or
IL-4 when they are activated by TCR cross-linking kills these cells
(39), a process that is termed propriocidal apoptosis
(PA). PA can be mediated by either a Fas/Fas ligand or a TNF/TNFR
interaction (40). Fas/Fas ligand interactions are thought
to be most important for PA of CD4+ T cells
(40), whereas TNF/TNFR interactions are thought to be of
particular importance to PA of CD8+ T cells
(40). Consistent with this, anti-TNF- mAb has
little effect on IL-4 inhibition of anti-IgD-induced Ab production,
which depends on CD4+ T cell help and is
CD8+ T cell independent (Ref. 47 ;
and F. D. Finkelman, unpublished data). Unfortunately, we were
unable to determine whether IL-4 inhibits GM-induced
CD4+ T cell activation through a Fas-dependent
mechanisms because Fas-deficient lpr mice fail to develop a
substantial IgE or IgG1 response to GM and we were unable to
obtain a neutralizing anti-Fas ligand mAb.
It is likely that the effects of IL-4 on T cell activation that we have observed are not restricted to the artificial situation in which mice are injected with IL-4C, but occur naturally in situations in which large quantities of IL-4 are endogenously produced. Infections with some pathogens, such as gastrointestinal nematodes, cause substantial increases in IL-4 production (48). Systemic IL-4 levels are achieved during these infections that cause large increases in B cell class II MHC and CD23 expression (49, 50). Dose-response studies suggest that levels of IL-4 that are sufficient to have these effects on B cell surface molecule expression should be sufficient to make B cells resistant to mIg cross-linking-induced death (M. Mori and F. Finkelman, unpublished data) and prime T cells for PA.
The effects of IL-4 on B cell resistance to mIg cross-linking and Fas-mediated killing might be expected to increase the risk of autoimmune disease by inhibiting the deletion of autoreactive B cells. Mice that chronically overexpress IL-4 do, in fact, produce autoantibodies; however, the clinical effect of these autoantibodies is limited in mice that are not otherwise predisposed to develop severe systemic autoimmune disease (51). The results of our study suggest that the risk for autoimmunity that is imposed by the effects of IL-4 on B cells is counterbalanced by a second, immunosuppressive effect of IL-4 that causes deletion or inactivation of T cells presented with Ag in the presence of high IL-4 levels. Thus, although newly generated autoreactive B cells are less likely to be deleted when IL-4 levels are elevated, elevated IL-4 levels should also make it less likely that these B cells will be induced to differentiate into autoantibody-secreting cells by autoreactive CD4+ T cells, because elevated IL-4 levels increase the likelihood that newly generated autoreactive helper T cells will be deleted or made less responsive by contact with autoantigen.
In contrast to the effects of chronically elevated IL-4 levels, the production of IL-4 by CD4+ T cells during the course of a specific immune response should enhance B cell survival without interfering with T cell activation, because the suppressive effect of IL-4 on T cells is limited to the initial day of T cell activation. The relatively late production of IL-4 during a T cell-dependent immune response thus allows IL-4 producing T cells to escape its suppressive effect while limiting the bystander activation of other T cells, including self-reactive T cells.
Finally, we wish to point out that the immunosuppressive effect of IL-4 on T cell activation may have therapeutic applications. Experiments in an acute parent into F1 graft-vs-host disease (GVHD) model, in which graft CD8+ T cells develop into host-reactive CTLs that destroy the host hemopoietic and immune systems (52), indicate that treatment with IL-4 at the time of parental cell transfer eliminates transferred CD8+ T cells and prevents the development of GVHD (C. Via and F. Finkelman, manuscript in preparation). As would be predicted from our results in anti-IgD Ab-injected mice, this effect of IL-4 is seen only when IL-4 is administered on the day of cell transfer. Later administration of IL-4 either has no effect on GVHD or converts acute GVHD to chronic GVHD. Thus, it may be possible to use the T cell suppressive effect of IL-4 to inhibit development of acute, cytotoxic GVHD during bone marrow transplantation or to inhibit the development of graft-reactive host CTL that are involved in allograft rejection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Suzanne C. Morris, University of Cincinnati College of Medicine, Department of Internal Medicine, Division of Immunology, P.O. Box 670563, Cincinnati, OH 45267. E-mail address:
3 Abbreviations used in this paper: mIg, membrane Ig; GM, affinity-purified goat Ab specific for mouse IgD; GVHD, graft-vs-host disease; IL-2C, complexes of IL-2 and a neutralizing anti-IL-2 mAb that have long-acting IL-2 activity in vivo; IL-4C, complexes of IL-4 and a neutralizing anti-IL-4 mAb that have long-acting IL-4 activity in vivo; PA, propriocidal apoptosis; ELISPOT, enzyme-linked immunospot.
Received for publication August 3, 1999. Accepted for publication December 1, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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