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*
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Department of Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267;
Immunology Disease Resistance Laboratory, Livestock and Poultry Sciences Institute, U.S. Department of Agriculture, Beltsville, MD 20705; and
§
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Further studies have examined the role of B7-1 vs B7-2 in providing costimulatory signals during immune responses. Both in vitro and in vivo studies have suggested that B7-2 costimulation favors T cell IL-4 production (5, 6, 7), while other studies have suggested that either B7-1 or B7-2 can provide the required signals (8, 9, 10). Recently, studies of B7-2 costimulatory requirements were examined in several type 2 immune responses to infectious pathogens. Anti-B7-2 Ab treatment blocked the type 2 response to Schistosoma mansoni (11) and L. major (12), while type 2 responses to H. polygyrus were inhibited only following combined anti-B7-1/anti-B7-2 Ab administration (13). These findings suggest that B7-2 requirements during the Th2 immune response may differ with different infectious pathogens. However, the use of blocking anti-B7-1 and anti-B7-2 Abs may be associated with incomplete blocking, particularly at later stages of the immune response when these hamster and rat Abs, acting as immunogens, may induce inhibitory levels of neutralizing anti-rat and anti-hamster Abs. It is also possible that anti-B7-1/B7-2 Abs may be stimulatory since differences were observed following in vivo administration of whole Ab vs Fab' fragments (14), presumably because the Fab' fragments cannot cross-link Ag. Alternatively, the short half-life of Fab' fragments or immune responses to these proteins, which are often administered at high doses, may contribute to differences observed with whole Ab administration. The recent development of mouse strains lacking B7 molecules has provided a useful model for comparison with the effects of blocking Abs. Studies with these mice have indicated that either B7-1 or B7-2 can support germinal center (GC)3 formation and serum IgG responses to immunization with trinitrophenyl keyhole limpet hemocyanin plus CFA. In contrast, in the absence of adjuvant, B7-2 interactions are required to induce humoral immunity (9). In vivo studies of B7 molecules have primarily focused on the role of B7 molecules during the initiation stage of the immune response, while few reports (15) have examined whether B7-2 interactions are important after the development of effector T cells.
Our previous studies of the chronic type 2 response to the murine
parasite, H. polygyrus, have demonstrated that the combined
administration of anti-B7-1 and anti-B7-2 Abs blocked the
initial type 2 mucosal immune response, while administration of either
Ab alone had little effect (13). The H. polygyrus immune
response includes: elevations in TCR-
/ß+ T cell IL-4
production; T cell-dependent and -independent elevations in IL-3, IL-5,
and IL-9 mRNA; B cell proliferation and differentiation that results in
marked increases in serum IgG1 and IgE; and pronounced increases in
mesenteric lymph node (MLN) and GC formation (16, 17). IL-3, IL-5, and
IL-9 are elevated within 6 h after oral inoculation, while IL-4,
primarily derived from CD4+, TCR-/ß+ T
cells, is not elevated until 4–6 days. By day 14, pronounced
T-dependent elevations in serum IgE, IgG1, and MLN GC formation are
evident. In the chronic primary response to this murine pathogen, the
worms are not expelled but continue to stimulate a type 2 response for
several weeks. Although not host-protective, the CD4+ T
cell-dependent immune response does effectively reduce worm fecundity
as measured by adult worm egg production (18).
To directly examine whether B7-2 is required for the initiation or subsequent progression of the type 2 immune response, B7-2-/- mice were immunized with the nematode parasite, H. polygyrus. Our studies show that effector Th cell function and the associated type 2 immune response are not initially inhibited in B7-2-deficient mice, consistent with our previous studies with blocking Abs (13). However, as the immune response progressed, it became increasingly impaired. At 2 wk after infection, increases in T cell cytokine expression were markedly inhibited. Between days 14 and 24 after infection, serum IgE levels and GC formation also became markedly reduced in H. polygyrus-inoculated B7-2-/- mice compared with H. polygyrus-inoculated B7-2+/+ mice, although IgG1 levels remained comparable. These findings indicate variation in B7-2-dependence of different parameters of the type 2 response and demonstrate a requirement for B7-2 interactions after the development of Th effector cells to sustain the type 2 immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Wild-type, B7-2-/- BALB/c mice were used in our experiments. The experiments herein were conducted according to the principles set forth in the Guide for the Care and Use of Laboratory Animals, Institute of Animal Resources, National Research Council, Department of Health, Education and Welfare (NIH)78-23. Infective, ensheathed third-stage larvae of H. polygyrus (specimens on file at the U.S. National Parasite Collection, U.S. National Museum Helminthological Collection no. 81930, Beltsville, MD) were propagated and stored at 4°C until used. Mice were inoculated orally with 200 third-stage larvae by using a ball-tipped feeding tube (16). Adult worm numbers and egg production were quantitated as previously described (18).
Antibodies
Abs and reagents used for the in vivo cytokine intervention experiments included hamster anti-mouse B7-1 (16-10A1) (19) and control normal hamster IgG. The anti-B7-1 hybridoma was grown as ascites in athymic nude mice. The mAb was purified by salt fractionation, saving the fraction that was soluble in 25% saturated ammonium sulfate but precipitated in 50% saturated ammonium sulfate, followed by dialysis against 0.05 M Tris (pH 8.3) and cation exchange chromatography on DEAE-cellulose (DE-52; Whatmann; PGC Scientific, Gaithersburg, MD), using a discontinuous gradient of decreasing pH and increasing ionic strength to elute the column. Fractions were pooled, based on A280, and tested by gel immunodiffusion for reactivity with an anti-hamster IgG antiserum. The positive pool was then concentrated by pressure ultrafiltration and dialyzed against 0.15 M NaCl. The control hamster IgG was purified from normal hamster serum (Pel-Freez Biologicals, Rogers, AR) by the same process. After inoculation with H. polygyrus, mice were injected i.v. via the tail vein with 100 µg of anti-B7-1 or normal hamster IgG on days 0 and 4 after H. polygyrus inoculation for the day 8 timepoint, days 0, 4, and 7 for the day 14 timepoint, and days 0, 4, 7, 14, and 21, for the day 24 timepoint. Alternatively, mice were administered 200 µg of recombinant murine CTLA-4Ig (20) or the control fusion protein L6 on days 0 and 1 after H. polygyrus inoculation. For immunohistology, we used anti-CD4 (PharMingen, San Diego, CA) and the anti-Fc receptor Ab, 24G2 (21).
Immunohistological analysis
The procedure used for immunohistological staining was as
described previously (13, 22, 23). Briefly, MLN were collected
individually from mice in each treatment group on days 8, 14, and 24
after H. polygyrus inoculation, and sections were cut
serially at 8 µm and stored at -70°C. CD4+ T cells
were stained with biotinylated anti-CD4 mAb (L3T4; PharMingen)
followed by streptavidin-alkaline phosphatase (Zymed Laboratories, San
Francisco, CA), and GC B cells were stained with horseradish peroxidase
conjugated to peanut agglutinin (HRP-PNA; ICN Biomedicals, Aurora, OH).
The phosphatase was developed first with naphthol-AS-MX phosphate/Fast
Blue BB base (Sigma, St. Louis, MO), and the peroxidase was developed
with 3-amino-9-ethyl carbazole (Sigma). GC formation was quantified
volumetrically as determined by the ratio of PNA+ GC B
cells to total lymphoid tissue at three planes per MLN tissue (4–5
mice per group), as previously described (23). All photographs of the
tissue sections were taken at the same magnification (
x125).
Quantitation of serum Ig
Serum IgG1, IgG2a, and IgE levels were quantitated by ELISA.
Eosinophil counts
Eosinophils were counted from fresh blood samples with the Unopette test (Becton Dickinson, Rutherford, NJ).
Enzyme-linked immunospot (ELISPOT)
The frequency of IL-4-producing cells was determined by an ELISPOT assay, as described previously (22, 24). Briefly, individual wells of Immulon II (Dynex, Chantilly, VA) polystyrene 96-well flat-bottom plates were precoated with the anti-IL-4 "capture" Abs (BVD4.1D11.2) at a concentration of 10 µg/ml and incubated at 4°C overnight. After three washes with PBS-Tween 20 (0.05%) and three washes with PBS, plates were blocked with RPMI 1640 + 5% FBS for 1 h at 37°C. Single-cell suspensions (0.1 ml), adjusted to a concentration of 5 x 106 cells/ml, were added to the coated plates in serial 5-fold dilutions and incubated for 3 h at 37°C. Plates were then washed three times with PBS and three times with PBS-Tween 20, after which a biotinylated anti-IL-4 Ab (BVD6.24G2.3 for IL-4) was added to the wells at a concentration of 4 µg/ml. After incubation for 1 h at 37°C, the plates were washed three times with PBS, then then times with PBS-Tween 20, after which streptavidin-alkaline phosphatase (Jackson ImmunoResearch, West Grove, PA), diluted 1:2000 in PBS-Tween 20 + 5% FBS, was added to the wells and the plates incubated for 1 h at 37°C. Plates were then washed five times in PBS, after which 5-bromo-4-chloro-3-indolyl-phosphate (BCIP), at a concentration of 1 mg/ml in 0.1 M 2-amino-2-methyl-1-propanol with 0.6% low-melt agarose, was added to individual wells. After overnight incubation in a humid chamber, the number of blue spots in individual wells (where each spot represents a single cytokine-secreting cell) were enumerated by examining wells under a dissecting microscope.
RT-PCR
The coupled RT-PCR was used as previously described (25, 26). Tissues were homogenized in RNAzolB (Cinna/Biotecs, Friendswood, TX) at 50 mg of tissue/ml or 5 x 106 cells/ml. Purified RNA (10 µg) samples were reverse transcribed with Superscript RT (Bethesda Research Laboratories, Rockville, MD), and cytokine-specific primers were used to amplify selected cytokines (26). For each cytokine, the optimum number of cycles (i.e., the number of cycles that would produce a detectable quantity of cytokine product DNA that was directly proportional to the quantity of input mRNA) was determined experimentally. To verify that equal amounts of undegraded RNA were added in each RT-PCR within an experiment, the "housekeeping gene," hypoxanthine-guanine phosphoribosyl transferase (HPRT), was used as an endogenous internal standard and amplified with specific primers at the number of cycles at which a linear relationship between input RNA and final HPRT product was detected (26). Although HPRT values did not usually vary more than 2- to 3-fold, values for specific cytokines are normalized to HPRT values.
Amplified PCR product was detected by Southern blot analysis (25, 26), and the resultant signal was quantitated with a PhosphorImager (Molecular Dynamics, Sunnyvale, CA), which uses a phosphor screen instead of film to detect radioactive signals on the Southern blot (16, 25, 26).
Statistical analysis
Statistical differences (significance level of p
0.05) between groups were assessed using ANOVA and Tukey’s
t test for pairwise comparisons. The software program
SigmaStat (Jandel Scientific Software, San Rafael, CA) was used for all
statistical analyses.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although considerable evidence indicates that B7 ligands are required for the initiation of the type 2 immune response (17), the relative importance of B7-1 vs B7-2 remains uncertain (13). To directly test the requirement of B7-2 for the initiation and progression of the type 2 immune response, BALB/c B7-2-/- or BALB/c B7-2+/+ mice were orally inoculated with 200 third-stage H. polygyrus larvae, and, at days 8 and 14, mice were killed and assayed for type 2 cytokine production. In all experiments, treatment groups including anti-B7-1 mAb treatment of H. polygyrus-inoculated B7-2+/+ or B7-2-/- mice were used to confirm that the response observed remained B7-dependent in the B7-2-deficient mice.
Previous studies have shown that by day 8 after H. polygyrus
inoculation, elevations in most Th2 cytokines are at least partly T
cell-independent, while the sole detectable source of IL-4 elevations
is TCR-/ß+, CD4+ T cells (16). On day 8
after inoculation, the MLN was collected from the mice (five per
treatment group) and analyzed for IL-4 protein secretion by ELISPOT and
cytokine gene expression by quantitative RT-PCR. As shown in Fig. 1
, IL-4 secretion was markedly elevated
in H. polygyrus-inoculated B7-2+/+
mice, H. polygyrus-inoculated B7-2+/+ mice given
anti-B7-1 Ab, and H. polygyrus-inoculated
B7-2-/- mice. However, H.
polygyrus-inoculated B7-2-/- mice administered
anti-B7-1 Abs showed inhibited IL-4 secretion, indicating that IL-4
elevations in the B7-2-/- mice were B7-1-dependent.
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). IL-4 mRNA elevations were slightly
inhibited in B7-2-/- mice compared with
B7-2+/+ mice (p > 0.05), and
administration of anti-B7-1 Ab in inoculated B7-2-/-
mice decreased values close to those of untreated controls. Other type
2 immune response cytokines, which are derived from both T cell and
non-T cells at this stage of the response (16, 27), showed more
variability following anti-B7-1 Ab administration in both
B7-2+/+ and B7-2-/- H.
polygyrus-inoculated mice. By day 14 after H. polygyrus
inoculation, Th2 cytokines, in addition to IL-4, are largely derived
from CD4+ T cells (16). Th2 cytokine gene expression was
elevated in B7-2+/+ H. polygyrus-inoculated
mice but was inhibited, in most cases, to untreated control
levels (equal to 1) in inoculated B7-2-/- mice (Fig. 2).
Thus, these findings suggest that although B7-2 is not required for the
initiation of the T cell cytokine response, B7-2 is necessary for
sustaining the type 2 immune response at later stages. As we have
frequently observed, IL-4 secretion was not detectable at day 14 after
H. polygyrus inoculation (data not shown).
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Inhibition of Th2 cytokine gene expression at day 14 after
H. polygyrus inoculation suggested that effector
Th cell function was impaired at this late stage of the primary
response. To examine whether elevations in serum Igs were also
affected, serum IgG1 and IgE levels were measured at day 14 in the same
experiment where elevations in cytokine gene expression were analyzed.
As shown in Fig. 3, marked B7-1-dependent
serum IgG1 elevations were detected in H.
polygyrus-inoculated B7-2+/+ and B7-2-/-
mice, while serum IgE elevations were similar or slightly decreased
(p > 0.05) in H.
polygyrus-inoculated BALB/c B7-2-/- compared with
H. polygyrus-inoculated B7-2+/+ mice at day 14
after inoculation. Serum IgE elevations were also significantly
elevated (p < 0.05) in H.
polygyrus-inoculated B7-2+/+ mice administered
anti-B7-1 Abs compared to H. polygyrus-inoculated
B7-2+/+ mice administered control Abs. Further studies in
B7-1-deficient mice are required to distinguish whether this last
finding is a result of B7-1 blockade or a secondary effect resulting
from administration of exogenous Abs.
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, serum
IgE elevations were increasingly different between H.
polygyrus-inoculated B7-2-/- and B7-2+/+
mice at later stages of the response with an 30-fold difference
being detected at day 24 (p < 0.01). In
contrast, serum IgG1 levels differed only 2-fold throughout the
course of the response for H. polygyrus-inoculated
B7-2-/- and B7-2+/+ mice
(p > 0.05). There also remained a substantial
B7-1-dependent humoral component, since anti-B7-1 mAb treatment
markedly inhibited both serum IgE and IgG1 elevations in
B7-2-/- but not B7-2+/+ H.
polygyrus-inoculated mice (p < 0.01).
Serum IgG2a levels were not increased in any of the treatment groups
compared with untreated controls (data not shown).
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Previous studies with blocking anti-B7-2 Abs have indicated
that B7-2 ligand interactions are required for the development of GCs
in a T-dependent systemic immune response to a soluble protein Ag (23),
and other studies have suggested that B7-2 ligand interactions favor a
type 2 immune response (6, 28). We have recently demonstrated that
administration of both anti-B7-1 and anti-B7-2 Abs are required
to inhibit GC formation during the mucosal immune response following
oral inoculation with H. polygyrus (13). Our findings that
serum IgE but not serum IgG1 elevations were B7-2-dependent suggested
the possibility that GC formation might be reduced in B7-2-deficient
mice at later stages of the type 2 immune response. On days 8, 14, and
24 after H. polygyrus-inoculation, control and infected mice
were sacrificed, and MLN tissues were removed, sectioned, and stained
with PNA and anti-CD4 mAb to detect increases in GC size. To assess
overall GC volume in the MLN, quantitative volumetric analyses were
performed with individual MLN tissues, and the mean GC volume was
determined for each tissue. In H. polygyrus-inoculated
B7-2-/- mice, elevations in GC size were comparable to
inoculated B7-2+/+ mice at day 8 and day 14 after
inoculation, but were greatly reduced at day 24 after inoculation (Fig. 5 and Table I). At day 24, a slight elevation (still
<5%) in GC formation in H. polygyrus-inoculated
B7-2-/- mice compared with untreated
B7-2-/- mice was detectable.
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and Table I). These results
suggest that B7-1 is sufficient to provide the costimulatory signal
through CD28/CTLA-4 interactions required for MLN GC formation and
CD4+ T cell expansion at days 8 and 14 of the type 2 immune
response to H. polygyrus, but B7-2 interactions are required
by day 24. Adult worm fecundity is increased in H. polygyrus-inoculated B7-2-/- mice
Infection with H. polygyrus results in a chronic immune
response, which is associated with the continued presence of adult
worms in the gut. However, the T-dependent response does result in
reduced adult worm fecundity as measured by the total number of eggs
recovered from the intestine. To determine whether egg production was
still impaired in H. polygyrus-inoculated
B7-2-/- mice, at day 24 after inoculation, mice were
necropsied and the worm burden and fecundity measured. As shown in Fig. 6, the number of adult worms was comparable in H.
polygyrus-inoculated B7-2-/- and inoculated
B7-2+/+ mice; however, a marked increase in adult worm
fecundity was detected in H. polygyrus-inoculated
B7-2-/- mice (p < 0.01). These
findings suggest that B7-2 interactions are required to sustain the
T-dependent response associated with decreased adult worm egg
production during chronic H. polygyrus infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the immune response to infectious pathogens has not previously been examined in B7-2-/- mice, blocking anti-B7-1 and/or anti-B7-2 Abs have been used with varied results. Anti-B7-2 Abs blocked helminth-induced granuloma formation and Th2 cytokine expression following i.p. infection with eggs from S. mansoni (11), while administration of both anti-B7-1 and anti-B7-2 Abs was required to block the H. polygyrus response (13). However, the prolonged S. mansoni immunization protocol involving sensitization and challenge required a later time point for analysis of cytokine gene expression and effector Th2 cell function than assessed in the H. polygyrus immune response. Thus, it is possible that the down-regulatory effects of B7-2 deficiency may become more pronounced as the Th2 immune response progresses so that effector cell function becomes increasingly impaired at later stages of the response. Our findings in the B7-2-/- mice are consistent with this hypothesis, since Th2 cytokine expression was markedly reduced at day 14 after H. polygyrus inoculation, although it remained elevated at levels equivalent to those of B7-2+/+ mice at day 8 after H. polygyrus inoculation. Recent findings have also indicated that administration of anti-B7-2 Abs for up to 4 wk after infection down-regulates the Th2 immune response to L. major in BALB/c mice (28).
There are several possible explanations for the observation that B7-2 is required to sustain but not initiate the type 2 immune response. APCs important in sustaining the type 2 immune response after the development of effector Th cells may preferentially express B7-2. We consider this possibility unlikely, since previous findings have suggested that, although B7 ligand interactions are required for the initial development of IL-4-producing T cells and the associated type 2 response, they are not required for sustaining effector T cell function or the progression of the type 2 response in wild-type mice (3, 17, 29, 30). Delayed CTLA4Ig administration can actually enhance the H. polygyrus immune response in wild-type mice. (W.C.G. and J.F.U., unpublished observations). Another possibility is that decreased total B7 molecule expression in the B7-2-deficient mouse increases competition for B7 ligand binding, thereby favoring CTLA-4 signaling, since CTLA-4 has at least a 10-fold greater affinity for B7 molecules than CD28. B7-2 is often expressed at higher levels than B7-1 by APCs (31, 32), and, thus, decreasing B7-2 levels may be particularly effective in influencing the immune response. At initial stages of T cell activation and differentiation, a positive response would still occur since CTLA-4 is not usually expressed on resting T cells (33), however, as the response progressed, CTLA-4-mediated down-regulation would be favored. It is also possible that B7-1 and B7-2 differentially affect CTLA-4 or CD28 signaling. B7-1 and B7-2 bind different regions of CTLA-4, and B7-1 has a lower off rate than B7-2 (34, 35, 36), suggesting that it may affect CTLA-4 signaling differently. B7-1 transgenic mice, which express B7-1 (as well as B7-2) at high levels, have generalized immunosuppression, consistent with the hypothesis that B7-1 signaling favors down-regulation (37).
Formation of the GC microenvironment requires Th effector function and is an important site of memory B cell development, Ig isotype switching, and V(D)J hypermutation (38). Both our previous studies with blocking Abs and our current studies with B7-2-/- mice indicate that B7-1 can substitute for B7-2 at early stages of the H. polygyrus immune response, leading to increased GC formation and CD4+ T cell expansion in the MLN. (16). However, our current studies further demonstrate that at later stages of the immune response increased GC formation is B7-2-dependent, suggesting that CD4+ T cell effector function is impaired at these later stages of the type 2 immune response when B7-2 interactions are absent. Our findings that B7-2 deficiency caused marked reductions in serum IgE, but not IgG1, indicate differential regulation of B cell IgE and IgG1 secretion through B7 costimulatory molecule interactions. It is possible that B7 molecules may signal on B cells (39), although there is no direct evidence of B7 signaling, and the lack of homology in B7 cytoplasmic domains between species suggests this is unlikely (40, 41). It is also possible that B7-2 interactions with CD28/CTLA-4 on T cells prevents down-regulation of serum IgE but not IgG1 secretion at later stages of the response. Elevations in both serum IgE and IgG1 are CD4+ T cell-dependent (42) and blocked by CTLA4Ig administration in the H. polygyrus immune response (3). However, serum IgG1 elevations are IL-4-independent, while increased serum IgE is IL-4-dependent (43, 44), indicating that the increased permissiveness of IgG1 secretion is mediated by other, as yet unidentified, T-dependent factors. Our findings suggest that this component of T cell help is not down-regulated in the absence of B7-2.
In summary, our results demonstrate that either B7-1 or B7-2 can support the initiation of the type 2 immune response to H. polygyrus, but that B7-2 is required for the progression of the type 2 immune response. Our findings that B7-2 plays an important role after the development of effector Th cells provide a possible explanation for some of the differences hitherto reported on B7-2-dependence of the type 2 immune response. It will be important in future studies to determine the mechanism by which B7-2 functions during the progression stage of the immune response, including the individual roles of CD28 and CTLA-4 in regulating Th cell effector function at later stages of the chronic type 2 immune response.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. William C. Gause, Department of Microbiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799. E-mail address:
3 Abbreviations used in this paper: GC, germinal center; MLN, mesenteric lymph node; HPRT, hypoxanthine-guanine phosphoribosyl transferase; ELISPOT, enzyme-linked immunospot.
Received for publication November 4, 1998. Accepted for publication January 6, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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