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Sensitive1
*
Immunology Disease Resistance Laboratory, Livestock and Poultry Sciences Institute, U.S. Department of Agriculture, Beltsville, MD 20705;
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Genetics Institute, Cambridge, MA 02140;
§
Immunology and Inflammation, Bristol-Myers Squibb, Princeton, NJ 08543; and
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Department of Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267 and Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, but unexpectedly did not inhibit production of the
Th2 cytokine, IL-13. Blocking both IFN- and B7 restored protective
immunity, which was IL-13 dependent, but did not restore IL-4 or
associated IgE responses. Although IL-13 was required for worm
expulsion in mice in which both IFN- and B7 were blocked, IL-4 could
mediate expulsion in the absence of both IL-13 and IFN-. These
studies demonstrate that 1) B7 costimulation is required to induce
IL-4, but not IL-13 responses; 2) IL-13 is elevated in association with
the IFN- response that occurs following inhibition of B7
interactions, but can only mediate IL-4-independent protection when
IFN- is also inhibited; and 3) increased IL-13 production, in the
absence of increased IL-4 production, is not associated with an IgE
response, even in the absence of IFN-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expulsion of gastrointestinal nematode parasites is particularly dependent on two members of the IL-4 cytokine subfamily, IL-4 and IL-13, which are encoded by closely linked genes within the mouse chromosome 11 cytokine gene cluster (6). Both are produced primarily by activated CD4+ T cells, and both have been shown by studies with cytokine-deficient mice to be normally required for protective immunity to Trichuris muris (7). IL-13 shares a common receptor with IL-4 (8, 9), which is primarily expressed by nonlymphocytes, but the regulation of IL-13 expression and function, including the extent to which IL-13 is IL-4 dependent, is not well understood (10, 11). One model suggests that IL-13 may be regulated by IL-4 production, because IL-4 is important in the priming and amplification of CD4+ T cells that then produce IL-13. Both cytokines could then subsequently contribute to protective immunity and induce worm expulsion (7). However, in some systems, it is clear the IL-13 can be expressed in the absence of IL-4 (11). Recent studies also suggest that IL-13 may contribute to the development of Th2 effector cells, because IL-13 knockout (KO)4 mice show impaired Th2 cytokine production by CD4+ T cells (12). The role of IL-13 in mediating murine IgE and IgG1 secretion is also controversial; although in vitro studies have failed to demonstrate IL-13-induced isotype switching of mouse B cells (13, 14), recent studies with IL-13 transgenic mice indicate that IgE and IgG1 secretion can occur via an IL-13-dependent, IL-4-independent pathway (15).
In this investigation, we examined the role of B7 ligand interactions
during the protective type 2 mucosal immune response to T.
muris. Administration of the murine CTLA4-Ig fusion protein (which
inhibits B7 ligand interactions) blocked increases in IL-4 and
inhibited the protective type 2 immune response but stimulated the
development of an alternative response, characterized by increases in
IFN- and IL-13, but not IL-4. However, blocking IFN- function in
CTLA4-Ig-treated, T. muris-infected mice restored a
protective response that resulted in worm expulsion but was
characterized by reduced levels of IL-4 and serum IgG1 and IgE. These
studies demonstrated a novel host-protective response that is mediated
by IL-13 in the absence of B7 ligand interactions and IL-4 function,
but is IFN- sensitive.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eight- to 12-wk-old BALB/c female mice (Charles River
Laboratories, National Cancer Institute, Frederick, MD) were used for
all studies of wild-type (WT) mice and as controls for the BALB/c
IFN--deficient mice. IFN--deficient mice (IFN-KO), which were
bred for over seven generations on a BALB/c background, were the
generous gift of Dr. Alan Sher (National Institute of Allergy and
Infectious Diseases, National Institutes of Health). IL-4KO, IFN-KO,
and IL-4/IFN- double KO were all on a BL/6 x 129
(F1) background, and WT siblings were used as
controls in these experiments. Normal and parasite-infected IFN-KO
mice consistently failed to express IFN-, while IL-4KO mice failed
to produce IL-4 in lymphocytes derived from the mesenteric lymph nodes
(MLN) and Peyer’s patches when measured by RT-PCR using primers
described below. 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 (National Institutes of
Health) 78–23.
Parasite and parasite Ags
Dr. Richard Grencis (University of Manchester, Manchester, U.K.)
originally provided infective T. muris eggs. Eight- to
10-wk-old female AKR mice (Charles River Laboratories) were inoculated
orally with 500 infective eggs, and adult worms were recovered from the
caecum and proximal colon by removal with insect forceps at 35 days
after inoculation. After 10 rounds of washing in sterile saline, viable
worms were placed in 24-well tissue culture plates containing RPMI 1640
medium with 100 U penicillin and 100 mg streptomycin and 2.5 mg
gentamicin/ml at 37°C in a humidified atmosphere of 95%
O2 and 5% CO2. Worms were
transferred to fresh media at 24-h intervals, and the conditioned media
and excreted eggs were centrifuged to recover supernatant containing
excretory/secretory (ES) Ags and eggs in the pellet. The eggs were
collected over 2 days and washed three times in sterile saline and
distributed to a 100-mm petric dish in filtered tap water. The egg
suspension was maintained at room temperature for 
35–40 days with
intermittent shaking of the dish and water replenishment. The eggs in
suspension were then adjusted to 5000 eggs containing larva/ml in
filtered tap water and maintained at 4°C until used for inoculation.
Parasite-conditioned supernatant fluids collected over 7 days were
concentrated and dialyzed against PBS with a concentrator (Amicon,
Danvers, MA), and protein concentration was determined by absorbance at
290 nm.
Worm burdens and fecundity
Larvae developing from 7 to 28 days after inoculation were isolated from the caecum and proximal colon of infected mice by gently removing fecal contents with a curved forceps and placing the tissue in 10 ml of HBSS containing 10 mM EDTA for 3 h at 37°C. The suspension was then vortexed for 45 s, and the larvae were counted with a dissecting microscopic at 15x magnification after they had settled in a petri dish. Adult worms developing later than 32 days after inoculation were counted directly while attached to the mucosa with the aid of a dissecting microscope. Worm fecundity was estimated by counting the number of T. muris eggs in a weighed sample of emulsified feces smeared on a microscope slide that was viewed using an inverted microscope at 40x magnification; total egg count was expressed as eggs per gram of feces.
Reagents
A rat IgG1 (XMG-6) mAb that neutralizes IFN- and a control
rat IgG1 anti-ß-galactosidase mAb (GL113) were produced in
pristane-primed nude mice and purified (16). Monoclonal
Abs were given i.v. in a tail vein at a concentration of 1 mg at weekly
intervals starting on the day of inoculation of T. muris
eggs. The chimeric fusion protein, murine CTLA4-Ig, and its control,
L6, were used to block B7 ligand interactions (1) and were
administered at a dose of 200 µg. A soluble IL-13 receptor, A25
(
2-human Fc fusion protein; sIL-13R2-Fc), which has a higher
affinity for IL-13 than surface IL-13R1 and which has been shown to
block IL-13 function in vivo (17, 18, 19), was administered
i.v. in the orbital plexus at concentrations of 200 µg every other
day from day 13 to 19 after inoculation; human IgG was used as a
control (17).
Cell cultures
Single-cell suspensions were prepared from the MLN and spleens by routine methods (20). RBC were lysed by osmotic treatment with ACK lysis buffer (Biofluids, Rockville, MD). Cells were placed in RPMI 1640 medium supplemented with 10% FCS that had been heat inactivated for 30 min at 57°C, 2 mM glutamine, 100U/ml penicillin, 100 µg/ml streptomycin, and 10 mM HEPES. Cell populations were plated at 3–4 x 106 cells per well in 24-well plates and cultured with T. muris ES Ag at a final concentration of 10 µg/ml. All cell cultures were incubated at 37°C in an atmosphere of 5% CO2 in air. Cell-free supernatant fluids were harvested from these cell cocultures at 72 h, and cytokine concentrations were determined by cytokine-specific ELISAs.
Quantitation of IL-13
ELISAs were performed on supernatants from cultured cells using
a commercial kit according to the manufacturers instructions (R&D
Systems, Minneapolis, MN). Measurement of serum IL-13 levels was
performed with the same kit, except that polyclonal anti-murine
IL-13R2 Ab (L6108) was added during the primary incubation period to
a 1:10 or 1:100 dilution of serum samples at 4°C overnight. This
additional step has previously been shown to be necessary to maintain
assay sensitivity for measurement of serum IL-13 levels
(21).
Quantitation of serum Ig
Serum IgG1, IgG2a, and IgE levels were quantitated by ELISA (22).
Immunohistological analysis
The procedure used for immunohistological staining and germinal center (GC) quantitation was as described previously (2).
RT-PCR
The coupled RT/PCR reaction was used to quantitate differences between treatment groups as previously described (23, 24, 25). Briefly, tissues were homogenized in RNazol B (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. 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 reaction 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. Although HPRT values did not usually vary >2- to 3-fold, values for specific cytokines are normalized to HPRT values. Amplified PCR product was detected by Southern blot analysis, 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.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined the role of B7 ligand interactions in the development
of the type 2 cytokine response to the gastrointestinal nematode
parasite, T. muris. Two hundred micrograms of murine
CTLA4-Ig or the control fusion protein, L6, were administered at days 0
and 1 after inoculation. At days 8, 14, 21, and 28 after inoculation,
infected mice (five per treatment group) were examined for changes in
cytokine gene expression using an RT-PCR assay that quantitates
relative differences between treatment groups (23). As
shown in Fig. 1
, murine CTLA-4Ig blocked
IL-4 mRNA elevations at or below untreated levels at all time points
except day 29, when levels were 3-fold greater than untreated levels.
In contrast, IFN- gene expression was elevated by day 14 and rapidly
increased >10-fold over untreated controls by day 21. The levels of
IL-13 were at least as elevated in T. muris-infected mice
given CTLA4-Ig as in T. muris-infected mice administered L6,
suggesting that regulation of this cytokine was less B7 ligand
dependent than regulation of IL-4.
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, CTLA4-Ig administration inhibited
serum IgE elevations at all time points examined, whereas T.
muris-inoculated mice given the control fusion protein L6 showed
pronounced elevations in serum IgE levels by day 14. Serum IgG2a levels
were elevated in T. muris-inoculated mice given CTLA4-Ig
compared with T. muris-inoculated mice administered L6,
consistent with the deviation of the immune response from an
IL-4-dominant type 2 response to an IFN--dominant type 1 immune
response. To examine susceptibility to infection, the number of
developing larvae were counted in the different treatment groups. As
early as day 14 after inoculation, the total worm number was elevated
in T. muris-inoculated mice given CTLA4-Ig compared with
T. muris-inoculated mice given L6. By day 21, the control
L6-treated group had eliminated most of the larvae, while the
CTLA4-Ig-treated group still showed a significant worm burden at day 28
after inoculation (Fig. 1).
Blocking IFN- production in addition to B7 ligand interactions
restores protective immunity to T. muris
Although previous studies have suggested that the development of
the type 2 cytokine response requires B7 ligand interactions, the
marked up-regulation of IFN- in T. muris-infected mice
administered CTLA4-Ig suggested the possibility that this cytokine
might also influence the course of the response. BALB/c IFN-KO mice
were administered CTLA4-Ig or L6, and the protective immune response
was assessed at day 35 after inoculation. Although cytokine levels are
reduced and difficult to detect at this time point, it does permit a
more complete assessment of host protection because adult worm
development and egg production can be measured (26). As
shown in Fig. 2, worms and eggs were not
detected in T. muris-inoculated BALB/c WT mice administered
L6, demonstrating a protective immune response resulting in parasite
expulsion. Consistent with findings already discussed, protection was
abrograted in T. muris-inoculated BALB/c WT mice
administered CTLA4-Ig, as evidenced by high egg production and worm
number. In contrast, T. muris-inoculated IFN-KO mice
administered CTLA4-Ig expelled the worms, demonstrating restoration of
the protective immune response even though B7 interactions were
blocked. Similar results were obtained in experiments where mice were
administered either CTLA4-Ig only at the initiation (days 0 and 1) of
the response (data not shown) or throughout the experiment (days 0, 1,
12, 24) (Fig. 2). In addition, these experiments were repeated in WT
mice where IFN- function was blocked by administration of
anti-IFN- Ab. Results in the WT mice were consistent with
studies performed in the IFN-KO mice: anti-IFN- mAb restored
protection in CTLA4-Ig-treated T. muris-infected BALB/c mice
(data not shown). We have also shown that protection is abrograted in
BALB/c B7-2KO and BALB/c CD28KO T. muris-infected mice, and
in further studies protection was restored in T.
muris-infected CD28KO mice administered anti-IFN- Ab (data
not shown). These studies support our findings using the B7 antagonist,
CTLA4-Ig, in WT mice and suggest that B7-2 and CD28 are required for
the development of the protective response to T. muris. The
requirements for IFN- to maintain susceptibility to T.
muris when B7 ligand interactions are blocked suggested a novel
regulatory role for IFN- in the development of a B7
ligand-independent protective response.
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blockade lacks many features of the typical type 2
immune response, but is associated with pronounced increases in IL-13
To examine the nature of the IFN--sensitive, B7
ligand-independent host protective response, T.
muris-inoculated mice were administered CTLA4-Ig and
anti-IFN- Abs and studied at an early time point after infection
(day 21), when cytokine production is optimally elevated. T.
muris-infected BALB/c mice (five per treatment group) were
administered CTLA4-Ig and/or anti-IFN- Abs; an additional
control group was given both L6 and GL113, the control mAb for
anti-IFN- mAb. Consistent with our previous findings, in this
experiment all treatment groups had worm counts of five or less except
for T. muris-infected WT mice administered CTLA4-Ig, which
had a large worm burden (75 ± 10.5).
Analysis of cytokine gene expression revealed sustained blockade of
IL-4 elevations in T. muris-infected mice administered
anti-IFN- Ab as well as CTLA4-Ig. In contrast, IL-13 was
markedly elevated in T. muris-inoculated mice administered
either CTLA4-Ig or the combination of CTLA4-Ig and anti-IFN- Ab.
IFN- gene expression was also increased in T.
muris-inoculated mice given CTLA4-Ig (Fig. 3A). Similar results were
observed in an experiment in which IFN- gene deletion was used
instead of anti-IFN- mAb treatment (Fig. 3B). In both
experiments, IL-9, IL-10, and TNF- gene expression remained at
untreated levels for all treatment groups at the time points studied
(data not shown). To examine whether IL-4 function was inhibited, serum
IgE, and also IgG1 levels, were assessed. Both Ab isotypes were
inhibited in T. muris-inoculated mice administered either
CTLA4-Ig or CTLA4-Ig plus anti-IFN- Abs compared with infected
mice given control Abs or anti-IFN- Ab alone (Fig. 4). In addition, GC formation in the MLN
was increased in T. muris-infected mice and blocked in all
groups receiving CTLA4-Ig (data not shown). These findings indicate
that the protective mucosal immune response to T. muris can
develop even when IL-4 and the humoral immune response usually
associated with the type 2 immune response to T. muris is
inhibited.
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blockade, serum IL-13 levels (Fig. 5A) and IL-13 protein in
supernatants from cells restimulated in vitro with T. muris
ES products (Fig. 5B) were assayed. In both assays,
increased IL-13 was detected in T. muris-infected mice given
CTLA4-Ig plus anti-IFN- compared with T.
muris-infected mice given control Abs or CTLA4-Ig.
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function and B7 interactions are blocked is
IL-13 dependent
Our findings that IL-13, but not IL-4, is elevated in T.
muris-infected mice administered CTLA4-Ig plus anti-IFN-
suggested that the protective response observed in this treatment group
may be mediated by IL-13. T. muris-infected mice given
CTLA4-Ig and anti-IFN- Ab were administered soluble
IL-13R2-Fc fusion protein (A25), which
neutralizes IL-13 (17, 18), or, as a control, human IgG,
every other day from 13 to 19 days after inoculation with eggs. As in
previous experiments, IFN- blockade restored the protective response
that was abrogated when T. muris-infected mice were
administered CTLA4-Ig alone (Fig. 6A). However, additional
administration of A25 was associated with a dramatic increase in worm
number, comparable to that observed in T. muris-infected
mice administered CTLA4-Ig alone (Fig. 6A). These results
demonstrate that the protective B7-independent immune response to
T. muris that is regulated by IFN- is mediated by
IL-13.
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dKO mice but not IL-4KO
mice
The observation that IL-13 can mediate protection following B7
blockade and IFN- neutralization suggested that IL-13 can mediate
protection independently of IL-4 if IFN- is blocked. To test this
directly, IL-13-mediated protection was compared between IL-4KO and
IL-4/IFN-dKO T. muris-infected mice. As shown in Fig. 6B, IL-4KO mice showed reduced protection compared with WT
T. muris-infected mice. However, IL-4/IFN- dKO T.
muris-infected mice showed enhanced protection that was inhibited
by IL-13 blockade following A25 administration. The incomplete
protection observed in the WT infected mice was due to their genetic
background, BL/6 x 129, which shows somewhat more susceptibility
than BALB/c and is the genetic background used in all treatment groups
in this experiment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, while either IL-4 or
IL-13 can mediate worm expulsion in the absence of IFN-; and 3) IL-4
is required for the induction of an IgE response even when IFN- is
blocked and sufficient IL-13 is produced to mediate worm expulsion.
These three observations will be discussed individually. Regulation of IL-4 and IL-13 responses
IL-4 gene expression and function, as measured by serum IgE
elevations, was strongly suppressed by blocking B7 with CTLA4-Ig in
T. muris-inoculated mice. However, in the same experiments,
increased IL-13 gene expression and protein expression were observed.
Although differences in B7 costimulatory requirements for IL-4 vs IL-13
have not been reported, recent studies have suggested that these two
closely linked genes can be independently regulated. These include
previous demonstrations that IL-4 and IL-13 can be produced at
different times during a type 2 cytokine response (27, 28), that IL-13 can be associated with a type 1 cytokine
response (29, 30), that IL-13 can enhance IL-12 production
in mice infected with Listeria monocytogenes
(30), and recent studies indicating independent regulation
of IL-4 and IL-13 by transcription factors including c-maf
(31). However, our results assessing IL-13 gene expression
and serum IL-13 appear to differ from observations that T cells from
S. mansoni- or T. muris-infected IL-4-deficient
mice make little IL-13 when restimulated in vitro with Ag or mitogen,
respectively (7, 21). Interestingly, MLN IL-13 gene
expression and serum IL-13 protein elevations were comparable in
T. muris-infected mice administered CTLA4-Ig or L6, while in
the in vitro restimulation assays IL-13 was actually reduced following
B7 blockade (Fig. 5). This is consistent with the possibility that IL-4
or costimulation may be more important for IL-13 production following
restimulation or challenge. However, all three assays (gene expression,
serum levels, and in vitro restimulation with Ag), as well as the
restoration of parasite expulsion following neutralization of IL-13 in
vivo, indicate that IL-13 is elevated and functional in vivo when
IFN-, as well as B7, interactions are inhibited.
The reduced IL-4 and elevated IFN- expression following CTLA4-Ig
administration of T. muris-infected mice is consistent with
previous studies, suggesting that B7 ligand interactions are
preferentially required for the in vivo type 2 immune response
(3, 4) and for the in vitro development of IL-4-producing
T cells (32). These studies also support the "strength
of signal model," suggesting that signals through B7 costimulatory
molecules can promote the type 2 response and associated IL-4
elevations (33). However, IL-13 apparently does not follow
this model because it can be elevated in the absence of B7
costimulation and when IFN- is increased. In contrast, we have
recently found that administration of CTLA4-Ig to H.
polygyrus-inoculated mice inhibits IL-13, as well as IL-4,
expression (W. C. Gause and J. Urban, manuscript in preparation).
An alternative IFN--dominant response does not occur when B7
interactions are blocked during H. polygyrus infection
(2). It is thus possible that the IFN- response
observed following B7 blockade during T. muris infection is
accompanied by factors that also promote IL-13 production. Indeed,
recent findings suggest that IL-18, a cytokine associated with IFN-
responses, can also stimulate IL-13 expression (34).
Interactions between IL-4, IL-13, and IFN- in mediating worm
expulsion
Our findings show that IFN- has an important and specific
influence on worm expulsion following T. muris infection: in
its absence, either IL-4 or IL-13 can induce expulsion, while both type
2 cytokines are required for worm expulsion in its presence. The marked
IL-13 elevations observed following B7 and IFN- blockade may be
required for the development of an effective protective response in the
absence of IL-4. However, it is also possible that IFN- may inhibit
type 1 or type 2 IL-4R signaling and/or expression; recent findings
suggest that IFN- may indirectly inhibit IL-4R signaling by
up-regulation of SOCS-1 (35). Alternatively, IFN- may
have a direct inhibitory effect on worm expulsion by interfering with
IL-4 and IL-13 action on nonlymphoid target cell populations in the
intestine that mediate worm expulsion. IL-4 and IFN- have previously
been shown to have opposing effects on other target cells, including
MHC II expression by B cells (36, 37). Direct effects of
IFN- on such target cell populations may also explain the decreased
worm burden found in IL-13 antagonist-treated IL-4/IFN-
double-deficient mice, as compared with IL-13 antagonist-treated
IL-4-deficient mice.
Regulation of Ig isotype responses
Until recently, the failure of IL-13 to induce an IgE response in
CTLA4-Ig-treated, T. muris-infected mice would have been
thought a consequence of the perceived failure of murine B cells to
express the type 2 IL-4 receptor (28). Recently, however,
high serum IgE levels have been demonstrated in
IL-13-overproducing/IL-4-deficient transgenic mice (15).
This observation demonstrates that, at least under some circumstances,
B cells must be able to express the type 2 IL-4 receptor and IL-13 must
be able to stimulate B cells to switch to the production of IgE. Our
current observation puts the transgenic data into perspective by
suggesting that even under conditions in which considerable IL-13 is
being produced (a sufficient quantity to mediate worm expulsion) and
the suppressive effects of IFN- on switching to IgE are absent, IL-4
is still required to induce a detectable increase in serum IgE levels.
This result is consistent with studies that demonstrate reduced IgE
production in T. muris-infected IL-4-deficient mice, but
normal IgE responses in infected IL-13-deficient mice (7).
Possibly, murine B cells can be induced to express signaling type 2
IL-4 receptors under some circumstances, but this requires persistent
expression of higher levels of IL-13 than are found in mice infected
with T. muris.
Taken together, our results demonstrate that an alternative cytokine
response develops following B7 blockade of T. muris-infected
mice that is associated with increases in both IL-13 and IFN- and
that neutralization of IFN- during this response is able to induce
IL-13-mediated worm expulsion. This suggests that IL-13 may be
associated with either type 1 or type 2 cytokine responses in the mouse
and demonstrates that this cytokine can mediate protection against
gastrointestinal helminthic parasites in the absence of B7-dependent
components of the type 2 cytokine response.
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Footnotes |
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2 H.F. and Q.L. contributed equally to this work.
3 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:
4 Abbreviations used in this paper: KO, knockout; WT, wild type; MLN, mesenteric lymph node; HPRT, hypoxanthine-guanine phosphoribosyl transferase; GC, germinal center; ES, excretory/secretory.
Received for publication December 10, 1999. Accepted for publication February 10, 2000.
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1 promotes IgG2a and IgG2b production by murine germinal center B cells. J. Immunol. 163:1153. regulates the isotypes of Ig secreted during in vivo humoral immune responses. J. Immunol. 140:1022.[Abstract]
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Q. Liu, C. Arseculeratne, Z. Liu, J. Whitmire, M. J. Grusby, F. D. Finkelman, T. N. Darling, A. W. Cheever, J. Swearengen, J. F. Urban, et al. Simultaneous Deficiency in CD28 and STAT6 Results in Chronic Ectoparasite-Induced Inflammatory Skin Disease Infect. Immun., July 1, 2004; 72(7): 3706 - 3715. [Abstract] [Full Text] [PDF]
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M. Morimoto, M. Morimoto, J. Whitmire, S. Xiao, R. M. Anthony, H. Mirakami, R. A. Star, J. F. Urban Jr, and W. C. Gause Peripheral CD4 T Cells Rapidly Accumulate at the Host:Parasite Interface during an Inflammatory Th2 Memory Response J. Immunol., February 15, 2004; 172(4): 2424 - 2430. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Mentink-Kane, B. A. Jacobson, A. W. Cheever, M. J. Whitters, M. E.P. Goad, A. Wong, M. Collins, D. D. Donaldson, M. J. Grusby, et al. Regulation and Function of the Interleukin 13 Receptor {alpha} 2 During a T Helper Cell Type 2-dominant Immune Response J. Exp. Med., March 17, 2003; 197(6): 687 - 701. [Abstract] [Full Text] [PDF]
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Z. Liu, Q. Liu, J. Pesce, J. Whitmire, M. J. Ekkens, A. Foster, J. VanNoy, A. H. Sharpe, J. F. Urban Jr., and W. C. Gause Nippostrongylus brasiliensis Can Induce B7-Independent Antigen-Specific Development of IL-4-Producing T Cells from Naive CD4 T Cells In Vivo J. Immunol., December 15, 2002; 169(12): 6959 - 6968. [Abstract] [Full Text] [PDF]
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L. R. Schopf, K. F. Hoffmann, A. W. Cheever, J. F. Urban Jr., and T. A. Wynn IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection J. Immunol., March 1, 2002; 168(5): 2383 - 2392. [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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